SOLID DOSAGE FORM

FORME DE DOSAGE SOLIDE

English Abstract

There is provided a solid dosage form adapted for the release of a biologically active material in the oral cavity wherein the dosage form comprises at least one biologically active material, and at least one matrix forming agent, wherein the dosage form substantially dissolves in the oral cavity. A method of producing the same and a kit comprising the same are also provided.

French Abstract

La présente invention concerne une forme de dosage solide prévue pour la libération d'une matière biologiquement active dans la cavité buccale, la forme de dosage comprenant au moins une matière biologiquement active et au moins un agent de formation de matrice, la forme de dosage se dissolvant sensiblement dans la cavité buccale. La présente invention concerne en outre un procédé de production de ladite forme de dosage solide et un kit la comprenant.

Claims

90
The embodiments of the invention in which an exclusive property or privilege
is
claimed are defined as follows:
1. A solid dosage form adapted for the release of a biologically active
material in
the oral cavity wherein the dosage form comprises:
a) at least one biologically active material at a concentration from 1 to
45% by dry weight of the dosage form, and
b) at least one matrix forming agent comprising amylopectin at a
concentration from 2% to 17% by dry weight of the dosage form,
wherein the dosage form is a fast disintegrating and dissolving solid freeze-
dried wafer dosage form;
wherein the dosage form is adapted for the release of a biologically active
material in an oral cavity of a subject for sublingual administration;
wherein the dosage form is capable of substantially dissolving in the oral
cavity without leaving a residue of said dosage form in the oral cavity that
is
detectable by a subject, thereby avoiding the urge for the subject to swallow
the dosage form;
wherein the dosage form is capable of disintegrating in the oral cavity in a
time of less than 15 seconds and dissolving in the oral cavity in a time of
less
than 60 seconds;
wherein the dosage form is capable of delivering an effective plasma
concentration of the active material by providing a C max concentration that
is
lower than that reached by the equivalent intravenous administration of the
same active and a t max comparable to intravenous administration and
wherein the biologically active material is: at least one cyclic guanosine
monophosphate (cGMP) phosphodiesterase type 5 (PDE5) inhibitor, an
active material that binds to one or more adrenergic receptors, or an N-
methyl-D-aspartate receptor antagonist.

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2. The solid dosage form of claim 1, wherein the N-methyl-D-aspartate
receptor
antagonist is: dextromethorphan, dextrorphan or ketamine.
3. The solid dosage form of claim 1, wherein the active material that binds
to one
or more adrenergic receptors is adrenaline, or an adrenaline salt.
4. The solid dosage form of claim 1, wherein the cyclic guanosine
monophosphate (cGMP) phosphodiesterase type 5 (PDE5) inhibitor is sildenafil
or a
pharmaceutically acceptable salt thereof.
5. The solid dosage form of any one of claims 1 to 4, wherein the dosage
form
completely dissolves once placed in the oral cavity in a time period of: less
than 50
seconds; less than 40 seconds; less than 30 seconds; less than 20 seconds;
less
than 15 seconds; less than 10 seconds; less than 7.5 seconds; less than 5
seconds;
less than 4 seconds; less than 3 seconds; or less than 2 seconds after
administration of the dosage form.
6. The solid dosage form of any one of claims 1 to 5, wherein the dosage
form
provides an effective plasma concentration of the biologically active material
within a
period of no more than two hours, 30 minutes, 20 minutes, or 15 minutes.
7. A method to produce a solid freeze dried wafer dosage form adapted for
the
release of a biologically active material in the oral cavity of a subject for
sublingual
administration; wherein the dosage form is a fast disintegrating and
dissolving solid
freeze-dried wafer dosage form; wherein the dosage form is capable of
substantially
dissolving in the oral cavity without leaving a residue of said dosage form in
the oral
cavity that is detectable by a subject, thereby avoiding the urge for the
subject to
swallow the dosage form; wherein the dosage form is capable of disintegrating
in
the oral cavity in a time of less than 15 seconds and dissolving in the oral
cavity in a
time of less than 60 seconds; and wherein the dosage form is capable of
delivering

92
an effective plasma concentration of the active material by providing a C max
concentration that is lower than that reached by the equivalent intravenous
administration of the same active and a t max comparable to intravenous
administration, comprising the steps of:
a) combining at least one matrix forming agent comprising amylopectin at
a concentration from 2% to 17% by dry weight of the dosage form with
a biologically active material at a concentration from 1 to 45% to form
a homogeneous mixture; and
b) freeze drying the mixture to prepare the solid dosage form of the
present invention
wherein the biologically active material is: at least one cyclic guanosine
monophosphate (cGMP) phosphodiesterase type 5 (PDE5) inhibitor, an active
material that binds to one or more adrenergic receptors, or an N-methyl-D-
aspartate receptor antagonist.
8. The method of claim 7, wherein the N-methyl-D-aspartate receptor
antagonist
is: dextromethorphan, dextrorphan or ketamine, or a pharmaceutically
acceptable
salt thereof.
9. The method of claim 7, wherein the active material that binds to one or
more
adrenergic receptors is adrenaline, or an adrenaline salt.
10. The method of claim 7, wherein the cyclic guanosine monophosphate
(cGMP)
phosphodiesterase type 5 (PDE5) inhibitor is sildenafil or a pharmaceutically
acceptable salt thereof.
11. The method of any one of claims 7 to 10, wherein the dosage form
completely
dissolves once placed in the oral cavity in a time period of: less than 50
seconds;
less than 40 seconds; less than 30 seconds; less than 20 seconds; less than 15
seconds; less than 10 seconds; less than 7.5 seconds; less than 5 seconds;
less

93
than 4 seconds; less than 3 seconds; or less than 2 seconds after
administration of
the dosage form.
12. The method of any one of claims 7 to 11, wherein the dosage form provides
an
effective plasma concentration of the biologically active material within a
period of
no more than two hours, 30 minutes, 20 minutes, or 15 minutes.
13. A kit comprising:
a) a solid dosage form adapted for the release of a biologically active
material in the oral cavity of a subject for sublingual administration;
wherein the dosage form is a fast disintegrating and dissolving solid
freeze-dried wafer dosage form; wherein the dosage form is capable
of substantially dissolving in the oral cavity without leaving a residue of
said dosage form in the oral cavity that is detectable by a subject,
thereby avoiding the urge for the subject to swallow the dosage form;
wherein the dosage form is capable of disintegrating in the oral cavity
in a time of less than 15 seconds and dissolving in the oral cavity in a
time of less than 60 seconds; and wherein the dosage form is capable
of delivering an effective plasma concentration of the active material
by providing a C max concentration that is lower than that reached by
the equivalent intravenous administration of the same active and a t max
comparable to intravenous administration, wherein the dosage form
comprises:
(i) at least one biologically active material at a concentration from
1 to 45% by dry weight of the dosage form, and
(ii) at least one matrix forming agent comprising amylopectin at a
concentration from 2% to 17% by dry weight of the dosage
form; and
b) instructions for use

94
wherein the biologically active material is: at least one cyclic guanosine
monophosphate (cGMP) phosphodiesterase type 5 (PDE) inhibitor, an active
material that binds to one or more adrenergic receptors, or an N-methyl-D-
aspartate receptor antagonist.
14. The kit of claim 13, wherein the N-methyl-D-aspartate receptor antagonist
is:
dextromethorphan, dextrorphan or ketamine, or a pharmaceutically acceptable
salt
thereof.
15. The kit of claim 13, wherein the active material that binds to one or
more
adrenergic receptors is adrenaline, or an adrenaline salt.
16. The kit of claim 13, wherein the cyclic guanosine monophosphate (cGMP)
phosphodiesterase type 5 (PDE5) inhibitor is sildenafil or a pharmaceutically
acceptable salt thereof.
17. The kit of any one of claims 13 to 16, wherein the dosage form
completely
dissolves once placed in the oral cavity in a time period of: less than 50
seconds;
less than 40 seconds; less than 30 seconds; less than 20 seconds; less than 15
seconds; less than 10 seconds; less than 7.5 seconds; less than 5 seconds;
less
than 4 seconds; less than 3 seconds; or less than 2 seconds after
administration of
the dosage form.
18. The kit of any one of claims 7 to 11, wherein the dosage form provides
an
effective plasma concentration of the biologically active material within a
period of
no more than two hours, 30 minutes, 20 minutes, or 15 minutes.
19. A pharmaceutical composition comprising: the solid dosage form as defined
in
any one of claims 1 to 6, together with a pharmaceutically acceptable carrier.

95
20. Use of a solid dosage form in the manufacture of a medicament for
providing
allergy relief and anaphylaxis treatment, wherein the dosage form comprises:
a) at least one biologically active material comprising an active material
that binds to one or more adrenergic receptors at a concentration from
1 to 45% by dry weight of the dosage form, and
b) a matrix forming agent comprising amylopectin at a concentration from
2% to 17% by dry weight of the dosage form,
wherein the dosage form is a fast disintegrating and dissolving solid freeze-
dried wafer dosage form;
wherein the dosage form is adapted for the release of a biologically active
material in an oral cavity of a subject for sublingual administration;
wherein the dosage form is capable of substantially dissolving in the oral
cavity without leaving a residue of said dosage form in the oral cavity that
is
detectable by the subject, thereby avoiding the urge for the subject to
swallow
the dosage form;
wherein the dosage form is capable of disintegrating in the oral cavity in a
time of less than 15 seconds and dissolving in the oral cavity in a time of
less
than 60 seconds; and
wherein the dosage form is capable of delivering an effective plasma
concentration of the active material by providing a C max concentration that
is
lower than that reached by the equivalent intravenous administration of the
same active and a t max comparable to intravenous administration of an active
material that binds to one or more adrenergic receptors.
21. The use of claim 20, wherein an effective plasma concentration is achieved
within 120 minutes, within 30 minutes, or within 20 minutes or within 5
minutes.
22. Use of a solid dosage form in the manufacture of a medicament for
treating or
preventing hair loss, sexual dysfunction, pulmonary hypertension or psoriasis,
wherein the dosage form comprises:

96
a) at least one biologically active material comprising at least one cyclic
guanosine monophosphate (cGMP) phosphodiesterase type 5 (PDE5)
inhibitor at a concentration from 1 to 45% by dry weight of the dosage
form, and
b) a matrix forming agent comprising amylopectin at a concentration from
2% to 17% by dry weight of the dosage form,
wherein the dosage form is a fast disintegrating and dissolving solid freeze-
dried wafer dosage form;
wherein the dosage form is adapted for the release of a biologically active
material in an oral cavity of a subject for sublingual administration;
wherein the dosage form is capable of substantially dissolving in the oral
cavity
without leaving a residue of said dosage form in the oral cavity that is
detectable by the subject, thereby avoiding the urge for the subject to
swallow
the dosage form;
wherein the dosage form is capable of disintegrating in the oral cavity in a
time
of less than 15 seconds and dissolving in the oral cavity in a time of less
than
60 seconds; and
wherein the dosage form is capable of delivering an effective plasma
concentration of the active material by providing a C max concentration that
is
lower than that reached by the equivalent intravenous administration of the
same active and a t max comparable to intravenous administration of at least
one cyclic guanosine monophosphate (cGMP) phosphodiesterase type 5
(PDE5) inhibitor.
23. The use of claim 22, wherein an effective plasma concentration is achieved
within 120 minutes, within 30 minutes, or within 20 minutes.
24. Use of a solid dosage form in the manufacture of a medicament for
providing
pain relief and/or anaesthesia, treating or preventing depression and/or
addiction, or
treating an epileptic seizure, wherein the dosage form comprises:

97
a) at least one biologically active material comprising an N-methyl-D-
aspartate receptor antagonist at a concentration from 1 to 45% by dry
weight of the dosage form, and
b) a matrix forming agent comprising amylopectin at a concentration from
2% to 17% by dry weight of the dosage form,
wherein the dosage form is a fast disintegrating and dissolving solid freeze-
dried wafer dosage form;
wherein the dosage form is adapted for the release of a biologically active
material in an oral cavity of a subject for sublingual administration;
wherein the dosage form is capable of substantially dissolving in the oral
cavity
without leaving a residue of said dosage form in the oral cavity that is
detectable by a subject, thereby avoiding the urge for the subject to swallow
the dosage form;
wherein the dosage form is capable of disintegrating in the oral cavity in a
time
of less than 15 seconds and dissolving in the oral cavity in a time of less
than
60 seconds; and
wherein the dosage form is capable of delivering an effective plasma
concentration of an active material by providing a C max concentration that is
lower than that reached by the equivalent intravenous administration of the
same active and a t max comparable to intravenous administration of an N-
methyl-D-aspartate receptor antagonist.
25. The use of claim 24, wherein an effective plasma concentration is achieved
within 120 minutes, within 30 minutes, or within 20 minutes.
26. The use
of claim 24, wherein the C max is between 50 ng/mL and 130 ng/mL for
a 25 mg dose.
27. A solid porous freeze dried wafer dosage form adapted for the release of a
biologically active material in an oral cavity wherein the dosage form
comprises:

98
a) at least one biologically active material at a concentration of 0.02 to 95%
by dry weight of the dosage form; and
b) at least one matrix forming agent comprising amylopectin at a
concentration from 2% to 17% by dry weight of the dosage form;
wherein the dosage form is a fast disintegrating and dissolving solid freeze-
dried
wafer dosage form;
wherein the dosage form is adapted for the release of a biologically active
material
in an oral cavity of a subject for sublingual administration;
wherein the dosage form is capable of substantially dissolving in the oral
cavity
without leaving a residue of said dosage form in the oral cavity that is
detectable by
a subject, thereby avoiding the urge for the subject to swallow the dosage
form;
wherein the dosage form is capable of disintegrating in the oral cavity in a
time of
less than 15 seconds and dissolving in the oral cavity in a time of less than
60
seconds;
wherein the dosage form is capable of delivering an effective plasma
concentration
of the active material by providing a C max concentration that is lower than
that
reached by the equivalent intravenous administration of the same active and a
t max
comparable to intravenous administration and
wherein the biologically active material is selected from the following list:
opioid
analgesics; cardiac inotropic agents; anxiolytics or sedatives; proteins or
peptides;
beta-adrenergic blocking agents or beta blockers; complementary medicines;
anti-
inflammatory agents; anti-arrhythmic agents; nutritional agents or vitamins;
amino
acids or derivatives; antidepressants; analgesics; antihypertensives or
cardiovascular agents; hormones; anti-malarial agents.
28. The disintegrating and fast dissolving solid dosage form according to
claim 27,
wherein the:
.cndot. opioid analgesic is buprenorphine, naloxone, naltrexone, fentanyl,
sufentanil, alfentanil, remifentanil, or tapentadol;
.cndot. cardiac inotropic agent is digoxin;

99
.cndot. anxiolytic or sedative is melatonin, clozapine, midazolam or
olanzapine;
.cndot. protein or peptide is glutathione or papain;
.cndot. complementary medicine is cannabinoid;
.cndot. beta-adrenergic blocking agent or beta blocker is propranolol,
metoprolol or atenolol;
.cndot. analgesic and anti-inflammatory agent is dexmedetomidine, ketorolac
or tramadol;
.cndot. anti-arrhythmic agent is adenosine, diltiazem, or esmolol;
.cndot. nutritional agent or vitamin is B-vitamins (B2, B3, B6, B7, B8, B9,
B10,
B11, B12, B13), quercetin, malic acid or hyaluronic acid;
.cndot. amino acid or derivative is N-acetyl cysteine, cysteine or cystine;
.cndot. antidepressant is desipramine, clomipramine, dapoxetine,
mirtazapine,
fluoxetine, sertraline, paroxetine, asenapine, quetiapine, aripiprazole,
or risperidone;
.cndot. analgesic is ketamine;
.cndot. antihypertensive or cardiovascular agent is clonidine or verapamil;
.cndot. hormone is oxytocin, raloxifene or adrenaline;
.cndot. anti-malarial agent is artemisinin.
29. A pharmaceutical composition comprising: the solid dosage form of claim 27
or
28, and a pharmaceutically acceptable carrier.
30. A kit comprising:
a) a solid dosage form adapted for the release of a biologically active
material in the oral cavity of a subject for sublingual administration;
wherein the dosage form is a fast disintegrating and dissolving solid
freeze-dried wafer dosage form; wherein the dosage form is capable of
substantially dissolving in the oral cavity without leaving a residue of
said dosage form in the oral cavity that is detectable by a subject,

100
thereby avoiding the urge for the subject to swallow the dosage form;
wherein the dosage form is capable of disintegrating in the oral cavity in
a time of less than 15 seconds and dissolving in the oral cavity in a time
of less than 60 seconds; and wherein the dosage form is capable of
delivering an effective plasma concentration of the active material by
providing a C max concentration that is lower than that reached by the
equivalent intravenous administration of the same active and a t max
comparable to intravenous administration, wherein the dosage form
comprises:
(i) at least one biologically active material at a concentration from
1 to 45% by dry weight of the dosage form, and
(ii) at least one matrix forming agent comprising amylopectin at a
concentration from 2% to 17% by dry weight of the dosage
form; and
b) instructions for use
wherein the biologically active material is selected from the following list:
opioid
analgesics; cardiac inotropic agents; anxiolytics or sedatives; proteins or
peptides; beta-adrenergic blocking agents or beta blockers; complementary
medicines; anti-inflammatory agents; anti-arrhythmic agents; nutritional
agents
or vitamins; amino acids or derivatives; antidepressants; analgesics;
antihypertensives or cardiovascular agents; hormones; anti-malarial agents.
31. The kit of claim 30, wherein the:
.cndot. opioid analgesic is buprenorphine, naloxone, naltrexone, fentanyl,
sufentanil, alfentanil, remifentanil, or tapentadol;
.cndot. cardiac inotropic agent is digoxin;
.cndot. anxiolytic or sedative is melatonin, clozapine, midazolam or
olanzapine;
.cndot. protein or peptide is glutathione or papain;
.cndot. complementary medicine is cannabinoid;

101
.cndot. beta-adrenergic blocking agent or beta blocker is propranolol,
metoprolol or atenolol;
.cndot. analgesic and anti-inflammatory agent is dexmedetomidine, ketorolac
or tramadol;
.cndot. anti-arrhythmic agent is adenosine, diltiazem, or esmolol;
.cndot. nutritional agent or vitamin is B-vitamins (B2, B3, B6, B7, B8, B9,
B10,
B11, B12, B13), quercetin, malic acid or hyaluronic acid;
.cndot. amino acid or derivative is N-acetyl cysteine, cysteine or cystine;
.cndot. antidepressant is desipramine, clomipramine, dapoxetine,
mirtazapine,
fluoxetine, sertraline, paroxetine, asenapine, quetiapine, aripiprazole,
or risperidone;
.cndot. analgesic is ketamine;
.cndot. antihypertensive or cardiovascular agent is clonidine or verapamil;
.cndot. hormone is oxytocin, raloxifene or adrenaline;
.cndot. anti-malarial agent is artemisinin.

Description

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SOLID DOSAGE FORM
FIELD OF THE INVENTION
[0001] This
invention relates to dosage forms adapted for administration to a subject.
Preferably, the solid dosage forms have fast dissolution rates.
BACKGROUND
[0002)
Tablets are a common dosage form to deliver an agent to human beings via oral
administration. Drug delivery via the oral cavity mucosa, for example the
sublingual mucosa,
allows a rapidly dissolving drug to be absorbed by simple diffusion, directly
into the systemic
circulation via the jugular vein, bypassing the gastrointestinal tract and the
hepatic first-pass
effect. The sublingual route usually produces a fast and reliable onset of
action, and is more
suitable for fast dissolving dosage forms.
[00031 There
is an unmet need in the medical field for dosage forms, which have a rapid
dissolution rate in the oral cavity. The previous attempts to overcome the
problems
associated with solid dosages forms Include effervescent tablets, films,
chewable tablets,
disintegrants and wicicing agents. These dosage forms are particularly useful
for patients
who have difficulty in swallowing e.g. children end elderly people. There are
several
technologies used for preparing such dosage forms, including freeze-drying,
spray-drying,
tablet moulding and tablet compression.
= [0004] Freeze drying processes have been used to prepare fast
dissolving solid dosage
forms. Depending on the manufacturing process, the product obtained is
characterised by a
highly porous microstructure of the supporting matrix (i.e. mannitol, glycine,
lactose,
gelatines etc.) in which the active agent is homogeneously dispersed. This
technology
produces a product which rapidly dissolves in water or in the oral cavity;
however, the poor
physical integrity of its physical structure severely limits further
manufacturing operations
such as forming blister packs. Moreover, the freeze drying technology in
manufacturing
such dosage forms is the high production costs because of the lengthy duration
of each
freeze drying cycle (normally from 24 to 48 hours). The complexity of the
industrial plants is
another important factor which prejudices the large scale use of this
technology for the
development of rapidly dissolving tablets. In addition, the thermal shacks, as
a direct
consequence of each freeze drying cycle, might physically modify the physical-
chemical
properties of the outer membrane of microencapsulated particles.

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[0005] In the
freeze-drying processes, gelatine and other gelatine-related materials
have been used to formulate agents in fast dissolving dosage forms. Gelatine
is carrier or
structure-forming agent, and it is commonly used in preparing fast dissolving
forms for a
wide range of drugs. Gelatine provides strength to the dosage form, thus
preventing
cracking and break-up of the dosage form. This is especially a problem when
the dosage
form is being removed from the blister package. Gelatine is advantageous in
fast dissolving
drug from the dosage form because once the dosage form is placed In the oral
cavity it
provides rapid dissolution of the dosage form.
[0006] Gelatine is
a protein which is obtained by the partial hydrolysis of animal
collagenous tissue, such as skins, tendons, ligaments and bone. However, one
significant
problem with mammalian-derived gelatine is that it has a bland taste. This
results in the fast
dissolving dosage form requiring the use of sweeteners and flavours to hide
and mask the
taste of the gelatine component. A further problem with conventional mammalian
derived
gelatine is that it requires the use of heat to affect the gelatine solution_
This additional step
adds time and cost to the process of manufacture.
100071 An
additional problem with the use of gelatine-based material as fast dissolving
dosage form matrices Is that the gelatine can increase in viscosity of the
solution with time.
This can lead to processing difficulties. Moreover, the gelatine can lead to
homogeneity and
sedimentation problems associated with the gelatine solution during the
holding period.
Other disadvantages of gelatine formulations include being prone to bacterial
growth and
some individuals dislike the fact it is from animal origin.
[0008] Other agents
which have been used to replace gelatine in fast dissolving dosage
forms are starch and modified starches. One problem with starch is that it has
a particulate
feel for the patient when in the mouth and can lead to dissatisfaction for the
patient_ Many =
modified starches also result in this problem_ Furthermore, they are
expensive.
[0009] Ketarnine is
a rapid-acting, general anaesthetic approved only for intravenous
injection. In recent years there has been increasing interest in its use at
non-anaesthetic
doses as an adjunct In acute and chronic pain management. Its pain modifying
properties
are attributed to its antagonism at the N-methyl-D-aspartate (NMDA) receptor,
binding non-
competitively to the phencyclidine binding site. When administered at sub-
anaesthesla
levels, ketamine is effective at producing anatgesia and also demonstrates
opioid sparing
activity, although the mechanisms behind this remain poorly understood.
Ketamine's
analgesic efficacy correlates well with its inhibiting action on N-methyl-D-
aspartate receptor--
mediated pain facilitation and a decrease in activity of brain structures that
respond to
noxious stimuli. Therefore its utility in the management of acute pain is of
interest. Although

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parenteral administration of ketamine might provide almost instant pain
relief, this route may
not be suitable or convenient for the patient.
[00010) Cyclic guanosine monophosphate (cGMP) phosphodiesterase type 5 (PDE5)
Inhibitors are a class of compounds that reduce the level of cGMP degradation
in smooth
muscles, leading to smooth muscle relaxation and increased blood flow. The
most well-
known cyclic guanosine monophosphate (cGMP) phosphodiesterase type 5 (PDE5)
inhibitor
is sildenafil, specifically sildenafil citrate or Viagra . Sildenafil is
usually taken in the form of
a tablet about 30 minutes to four hours before sexual intercourse. However,
faster acting
delivery of sildenafil or other cyclic guanosine monophosphate (cGMP)
phosphodiesterase
type 6 (PDE5) inhibitors may be advantageous, particularly In their other use
as a treatment
for pulmonary hypertension.
[00011] Adrenaline is a hormone and a neurotransmitter used to treat a
number of
conditions including: cardiac arrest and other cardiac dysrhythmias resulting
in diminished or
absent cardiac output; anaphylaxis; superficial bleeding; and asthma,
bronchospasm and
croup. Adrenaline is often delivered via an autoinjector delivery system;
however, alternative
delivery systems for rapid delivery may be advantageous for those who cannot
safely
administer an autoinjector (such as children and those in care of children who
are unfamiliar
with an autoinjector device), and those who do not wish to use such a device.
[00012] Therefore, there is a need in the art for a fast dissolving dosage
form which
delivers a biologically active material such as an N-methyl-D-aspartate
receptor antagonist,
adrenaline or a cyclic guanosine monophosphate (cGMP) phosphodiesterase type 5
(PDE5)
inhibitor to a patient via oral administration, wherein the dosage form
rapidly dissolves in the
oral cavity of the patient, and wherein the dosage form does not use
substantial amounts of
mammalian gelatine.
SUMMARY OF THE INVENTION
[00013] According to one aspect of the present invention there is provided
a solid dosage .
, form adapted for the release of a biologically active material in the oral
cavity wherein the
dosage form comprises:
(a) at least one biologically active material. and
(b) at least one matrix forming agent, wherein the dosage form substantially
dissolves In .
the oral cavity.

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Preferably, the solid dosage form is a fast dissolving solid dosage form.
Preferably, the biologically active material is chosen from the list
comprising: at least one
cyclic guanosine monophosphate (cGMP) phosphodiesterase type 5 (PDE5)
inhibitor, an
active material that binds to one or more adrenergic receptors, and an N-
methyl-D-aspartate
receptor antagonist. Preferably, the N-methyl-D-aspartate receptor antagonist
is chosen
from the list comprising: dextromethorphan, dextrorphan or ketamine.
Preferably, the active
material that binds to one or more adrenergic receptors is adrenaline
(epinephrine), or an
adrenaline salt. Preferably, the cyclic guanosine monophosphate (cGMP)
phosphodiesterase type 5 (PDE5) inhibitor is sildenafil or a pharmaceutically
acceptable salt
thereof. Preferably, the sildenafil salt Is sildenafil citrate.
100014] Preferably, the dosage form is adapted to not leave a residue of
said dosage
form in the oral cavity that is detectable by the patient.
[00015] Preferably, the dosage form quickly disintegrates in the oral
cavity, and allows
the rapidly dissolving biologically active material to be absorbed by
diffusion through the oral
mucosa and directly into the systemic blood circulation system. By this
method, the hepatic
first-pass effect is avoided. Preferably, the dosage form is adapted to be
delivered directly
into the systemic circulation via the jugular vein, bypassing the
gastrointestinal tract and the
hepatic first-pass effect.
[00018] According to another aspect of the present invention there is provided
a method
to produce the solid dosage form of the present invention comprising the steps
of:
(a) combining at least one matrix forming agent with a biologically active
material to form
a homogeneous mixture; and
(b) freeze drying the mixture to prepare the solid dosage form of the present
invention.
[00017] Preferably, the method is a method to produce a fast dissolving
solid dosage
form.
[00018] Preferably, the biologically active material is chosen from the
list comprising: at
least one cyclic guanosine monophosphate (cGMP) phosphodiesterase type 5
(PDE5)
Inhibitor, an active material that binds to one or more adrenergic receptors,
and an N-methyl-
D-aspartate receptor antagonist. Preferably, the N-methyl-0-aspartate receptor
antagonist
Is chosen from the list comprising: dextromethorphan, dextrorphan or ketamine.
Preferably,
the active material that binds to one or more adrenergic receptors is
adrenaline, or an
adrenaline salt, Preferably, the cyclic guanosine monophosphate (cGMP)

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phosphodiesterase type 5 (PDE5) inhibitor is sildenafil or a pharmaceutically
acceptable salt
= thereof. Preferably, the sildenafil salt is sildenafil citrate.
[00019] According to another aspect of the present invention there is
provided a kit
comprising:
(a) the solid dosage form, wherein the dosage form comprises:
(I) at least one biologically active material, and
(ii) at least one matrix forming agent, and
(b) instructions for its use
wherein the dosage form substantially dissolves in the oral cavity.
Preferably, the solid
dosage form Is a fast dissolving solid dosage form_ Preferably, the
biologically active
material is chosen from the list comprising: at least one cyclic guanosine
monophosphate
(cGMP) phosphodiesterase type 6 (PDE5) inhibitor, an active material that
binds to one or
more adrenergic receptors, and an N-methyl-D-aspartate receptor antagonist.
Preferably,
the N-rnethyl-D-aspartate receptor antagonist is chosen from the list
comprising:
dextromethorphan, dextrorphan or ketamine. Preferably, the active material
that binds to
one or more adrenergic receptors is adrenaline, or an adrenaline salt.
Preferably, the cyclic
guanosine monophosphate (cGMP) phosphodiesterase type 5 (PDE5) inhibitor is
sildenala
or a pharmaceutically acceptable salt thereof. Preferably, the sildenafil salt
is sildenafil
citrate.
[00020] According to another aspect of the present invention there is
provided solid
dosage form adapted for the release of at least one cyclic guanosine
monophosphate
(cGMP) phosphodiesterase type 5 (PDE5) inhibitor in an oral cavity wherein
said dosage
form comprises:
(a) at least one cyclic guanosine monophosphate (cGMP) phosphodiesterase
type 6
(PDE5) inhibitor; and
(b) at least one matrix forming agent;
wherein said dosage form substantially dissolves in the oral cavity.
Preferably, the solid
dosage form is a fast dissolving solid dosage form. Preferably, the cyclic
guanosine
monophosphate (cGMP) phosphodiesterase type 5 (PDE6) inhibitor is sildenafil
or a
pharmaceutically acceptable salt thereof. Preferably, the sildenafil salt is
sildenafil citrate.

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6
[00021] According
to another aspect of the present invention there is provided a solid
dosage form adapted for the release of an active material that binds to one or
more
adrenergic receptors In an oral cavity wherein said dosage form comprises:
(a) an active material that binds to one or more adrenergic receptors; and
(b) at least one matrix forming agent;
wherein said dosage form substantially dissolves in the oral cavity.
Preferably, the solid
dosage form is a fast dissolving solid dosage form_ Preferably, the active
material that binds
to one or more adrenergic receptors is adrenaline, or an adrenaline salt.
[00022] According
to another aspect of the present invention there is provided a solid
dosage form adapted for the release of N-methyl-D-aspartate receptor
antagonist in an oral
cavity wherein said dosage form comprises:
(a) an N-methyl-D-aspartate receptor antagonist; and
(b) at least one matrix forming agent;
wherein said dosage form substantially dissolves in the oral cavity.
Preferably, the solid
dosage form Is a fast dissolving solid dosage form. Preferably, the N-methyl-D-
aspartate
receptor antagonist is chosen from the list comprising: dextromethorphan,
dextrorphan or
ketamine.
[00023] According
to another aspect of the present invention there is provided a wafer
comprising a solid dosage form adapted for the release of a biologically
active material In an
oral cavity_ Preferably, the solid dosage form is a fast dissolving solid
dosage form.
Preferably, the biologically active material is chosen from the list
comprising; at least one
cyclic guanosine monophosphate (cGMP) phosphodiesterase type 5 (PDE5)
inhibitor, an
active material that binds to one or more adrenergic receptors, and an N-
methyl-D-aspartate
receptor antagonist. Preferably, the N-methyl-D-aspartate receptor antagonist
is chosen
from the list comprising: dextromethorphan, dextrorphan or ketamine.
Preferably, the active
Material that binds to one or more adrenergic receptors is adrenatine, or an
adrenaline salt.
Preferably, the cyclic guanosine monophosphate (cGMP) phosphodiesterase type 5
(PDE5)
inhibitor is sildenafil or a pharmaceutically acceptable salt thereof.
Preferably, the sildenafil
salt is sildenafil citrate. The wafer may be accompanied by instructions for
Its use.
[00024) According to another aspect of the present invention, there is
provided a
pharmaceutical composition comprising the solid dosage form of the Invention.
Preferably,
the solid dosage form Is a fast dissolving solid dosage form.

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7
DISCLOSURE OF INVENTION
Solid Dosage Form
[000251 According to one aspect of the present invention, there is provided a
solid
dosage form adapted for the release of a biologically active material in the
oral cavity
wherein the dosage form comprises:
(a) at least one biologically active material, and
(b) at least one matrix forming agent,
wherein the dosage form substantially dissolves in the oral cavity.
[00026] Preferably,
the solid dosage form is a fast dissolving solid dosage form.
Preferably, the biologically active material is chosen from the list
comprising: at feast one
cyclic guanosine monophosphate (cGMP) phosphodiesterase type 5 (PDE5)
inhibitor, an
active material that binds to one or more adrenergic receptors, and an N-
methyl-D-aspartate
receptor antagonist.
1000271 Preferably,
the N-methyl-D-aspartate receptor antagonist is chosen from the list
comprising: dextromethorphan, dextrorphan or ketamine. if the antagonist is
ketamine,
preferably the ketamine is a ketamine salt, such as ketamine hydrochloride. In
one
embodiment, the ketamine is In the form of a racemic mixture of the R and 8
enantlomers.
Preferably, the ketamine is a mixture of two enantiomers R-(-) and S-(+).
[000281 Preferably,
the biologically active material that binds to one or more adrenergic
receptors is adrenaline, or an adrenaline salt.
[00029] Preferably, the cyclic guanosine monophosphate (cGMP)
phosphodiesterase
type 5 (PD55) inhibitor is sildenafil or a pharmaceutically acceptable salt
thereof. Preferably,
the sildenafil salt is sildenafil citrate.
[00030) In one
embodiment, the biologically active material is present in an amount by
dry weight of the solid dosage form selected from the group consisting of:
0.01 to 95%; 0.1
to 75% and 1 to 45% weight by dry weight of the dosage form.
[00031] Preferably,
the dosage form quickly disintegrates In the oral cavity, and allows
the rapidly dissolving biologically active material to be absorbed by
diffusion through the oral
mucosa and directly into the systemic blood circulation system. By this
method, the hepatic
first-pass effect is avoided, Preferably, the dosage form Is adapted to be
delivered directly

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into the systemic circulation via the jugular vein, bypassing the
gastrointestinal tract and the
hepatic first-pass effect.
[00032] By "fast
dissolving", It Is preferably meant that the dosage form substantially
dissolves once placed in the oral cavity in a time period selected from the
group consisting
of: less than 2 minutes; less than 1 minute; less than 50 seconds; less than
40 seconds; less
than 30 seconds; less than 20 seconds; less than 15 seconds; less than 10
seconds; less
than 7.5 seconds; less than 5 seconds; less than 4 seconds; less than 3
seconds; and less
than 2 seconds after administration of the dosage form. Preferably, the fast
dissolving
dosage form's dissolution rate is higher than the dissolution rates of
conventional dosage
forms.
[00033] More preferably, the "fast dissolving" solid dosage form completely
dissolves -
once placed in the oral cavity in a time period selected from the group
consisting of: less
than 2 minutes; less than 1 minute; less than 50 seconds; less than 40
seconds; less than
30 seconds; less than 20 seconds; less than 15 seconds; less than 10 seconds;
less than
7.5 seconds; less than 5 seconds; less than 4 seconds; less than 3 seconds;
and less than 2
seconds after administration of the dosage form.
[00034] By
"substantially", it is meant that at least 60% of the fast dissolving dosage
form
has been dissolved In the oral cavity in the time period selected. Preferably,
at least 65%,
70%, 76%, 80%, 86%, 90%, 95%, 96%, 97% or 98% of the fast dissolving dosage
form has
been dissolved in the oral cavity in the time period selected. Most
preferably, at least 99% of
=
the fast dissolving dosage form has been dissoWed in the oral cavity in the
time period
selected.
[00035] In a highly
preferred embodiment of the present invention, there Is no residue
remaining that is detectable by the patient of the dosage form of the present
invention after
administration. Preferably, the dosage form completely dissolves after oral,
preferably
sublingual, administration to the patient. As such, the subject has no urge to
swallow the
dosage form. In particular, the pharmaceutical composition may be, for
example, designed
for buccal or sublingual delivery.
= Active Agents
[00036] The
biologically active material includes active compounds, and compounds for
veterinary and human use, such as but not limited to: pharmaceutical actives,
neutraceuticals, cosmeceuticals, cosmetics, complementary medicines, natural
products,
foods, vitamins, nutrients, biologics, amino acids, proteins, peptides,
nucleotides, and

9
nucleic acids. In a preferred form the biologically active material is adapted
for oral
administration.
[00037] in a preferred embodiment of the invention, the biologically active
material is an
organic compound. In a highly preferred embodiment of the invention, the
biologically active
material is an organic, therapeutically active compound for human use. In
another
embodiment of the present invention, the biologically active material is an
inorganic
compound. When the biological active material is a drug. it can be of a
neutral species,
basic or acidic as well as salts of an acid or base. This invention is not
limited to any drug
specific class, application type, chemical type or function grouping.
[000381 The
biologically active material Is ordinarily an agent for which one of skill in
the
art desires improved fast dissolution for oral administration. The
biologically active material
may be a conventional active agent or dam.
100039) Examples of biologically active materials suitable for use in the
invention Include
actives, biologics, amino acids, proteins, peptides, nucleotides, nucleic
acids, and
analogues, homologs and first order derivatives thereof. The biologically
active material can
be selected from a variety of known classes of drugs, including, however not
limited to: anti-
obesity drugs, central nervous system stimulants, carotenoids, codlcosterolds,
elastase
inhibitors, anti-fungals, oncology therapies, anti-emetics, analgesics,
cardiovascular agents.,
anti-inflammatory agents, such as NSAIDs and COX-2 inhibitors, anthelmintics,
anti-
arrhythmic agents, antibiotics (including penicillins), anticoagulants,
antidepressants,
antidiabetic agents, anilepileptics, antihistamines, antihypertensive agents,
antimuscarinIc
agents, antimycobacterial agents, antineopiastic agents, immunosuppressantS,
antithyrold
agents, antiviral agents. anxiolytics, sedatives (hypnotics and neuroieptics),
astringents,
alpha-adrenerglo receptor blocking agents, beta-adrenoceptor blocicing agents,
blood
products and substitutes, cardiac Inotropic agents, contrast media, cough
suppressants
(expectorants and mucolytics), diagnostic agents, diagnostic imaging agents,
diuretics.
dopaminergics (antl-Parkinsonlan agents), haeMostatick itnmunologket agents,
lipid
regulating agents, muscle relaxants, parasympathomlmetics, parathyroid
cakitonin and
biphosphonates. prostagiandins, radio-pharmaceuticals, sex hormones (Including
steroids),
anti-allergic agents, stimulants and anoraks, sympathomimetics, thyroid
agents,
vasodilators, and xanthines.
00040) A description of these classes of biologically active materials and a
listing of
species within each class can be found in Martindale's 'The Extra
Pharmacopoeia', 31st
Edition (The Pharmaceutical Press, London, 1998), and the 'Physician's Desk
Reference'
(Goth Ed., 2005), both of which will be familiar to those of skill in
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the art. The active agents are commercially available and/or can be prepared
by techniques
known in the art.
1000411
Additionally, examples of suitable biologically active materials Include,
however
are not limited to, those listed below:
= Analgesics and anti-inflammatory agents: aloxiprin, auranofm,
azapropazone,
benorylate, diflunisal, etodolac, fenbufen, fenoprofen calcim, flurbiprofen,
ibuprofen,
indomethacin, ketoprofen, meclofenamic acid, mefenamic acid, nabumetone,
naproXen, oxaprozin, oxyphenbutazone, phenylbutazone, piroxicam, sulindac.
= Anthelmintics: albendazole, bephenium hydroxynaphthoate, cambendazole,
dichlorophen, ivermectin, mebendazole, oxamniquine, oxfendazole, oxantel
embonate, prazIquantel, pyrantel embonate, thiabendazole.
= Anti-arrhythmic agents: amiodarone HCI, disopyramide, flecalnide acetate,
quinkline sulphate.
= Anti-bacterial agents: benethamine penicillin, cinoxacin, clprofloxacin
HCI,
clarithromycln, clofazimine, cloxacillin, demeclocycline, doxycycline,
erythromycin,
ethionamide, imlpenem, nalidixic acid, nitrofurantoin, rifampicin,
spiramycin,
sulphabenzamide, sulphadoxine, sulphamerazine, sulphacetamide, sulphadiazine,
sulphafurazole, suiphamethoxazole, sulphapyridine, tetracycline, trimethoprim.
= Anti-coaoulants: dicoumarol, dipyridamole, nicoumalone, phenindione.
= Anti-depressants: amoxapine, ciclazindol, maprotiline HCI, mianserin
nortriptyline HCI, trazodonel-ICI, trimipramine maleate.
= Anti-diabetics: acetohexamlde, chlorpropamide, glibenclamide, gliclazide,
glipizide,
tolazamide, tolbutamide.
= Anti-epileptics: bedamide, carbamazepine, clonazepam, ethotoin, methoin,
methsuximide, methylphenobarbitone,
oxcarbazepine, paramethadione,
phenacemide, phenobarbitone, phenytoin, phensuximide, primidone, sulthiame,
valprolc acid.
= Anti-fungal agents: amphotericin, butoconazole nitrate, dotrimazole,
econazole
nitrate, fluconazole, flucytosine, griseofulvin, itraconazole, ketoconazole,
miconazole,
natamycin, nystatin, sulconazole nitrate, terbinafine HCI, terconazole,
tioconazole,
undecenoic acid.

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=
=
11 =.
= Anti-gout agents: allopurinol, probenecid, surphinpyrazone.
= Anti-hypertensive agents: amlodipine, benidipine, darodipine, dilitazem
HCI,
dlazoxide, felodipine, guanabenz acetate, indoramin, Isradipine, mlnoxidil,
nicardipine
nifedipine, nimodipine, phenoxybenzamine HCI, prazosin HCI, reserpine,
terazosin HCI.
= Anti-malarials: amodiaquine, chloroquine, chlorproguanil HCI,
halofantrine HCI,
mefloquine HCI, proguanif HCI, pyrimethamine, quinine sulphate.
= Anti-migraine agents: dihydroergotamine mesylate, ergotamine tartrate,
methysergide maleate, pizotifen maleate, sumatriptan succinate.
= Anti-muscarinic agents: atropine, benzhexol HCI, biperiden, ethopropazine
HCI,
hyoscine butyl bromide, hyoscyamine, mepenzolate bromide, orphenadrine,
oxyphencylcimine HCI, tropicamide.
= Anti-neoplastic agents and immunosuppressants: aminogiutethimide,
amsacrine,
azathioprine, busulphan, chlorambucll, cyclosporin, dacarbazine, estramustine,
etoposide, lomustine, melphalan, mercaptopurine, methotrexate, mitomycin,
mitotane, mitozantrone, procarbazine HCI, tamoxifen citrate, testolactone.
= Anti-protazoal agents:
benznidazole, clioquinol, decoquinate,
dilodohydroxyquinoline, diloxanide furoate, dinitolmide, furzolidone,
'metronidazole,
nimorazole, nitrofurazone, omidazole, tinidazole.
= Anti-thyroid agents: carbimazde, propylthiouracil.
= Anxiolvtic, sedatives, hypnotica and neuroleptics: alprazolam,
amylobarbitone,
barbitone, bentazepam, bromazepam, bromperidol; brotizolam, butobarbitone,
carbromal, chiordiazepoxide, chlormethiazole, chlorpromazine, clobazam,
clotiazepam, clOzapine, diazepam, droperidol, ethinamate, flunanisone,
flunitrazepam, fluopromazine, flupenthixol decanoate, fluphenazine decanoate,
flurazepam, haloperidol, lorazepam, lormetazepam, medazepam, meprobamate,
methaqualone, midazolam, nitrazepam, oxazepam, pentobarbitone, perphenazine
pimozide, prochlorperazine, sulpiride, temazepam, thloridazine, triazolam,
zopiclone.
= Beta-Blockers: acebutolol, alprenolol, atenolol, labetalol, metoprolol,
nadolol,
= oxprenoloi, pindolol, propranolol.
= Cardiac Inotrooic adents: amrinone. digitoxin, digoxin, enoximone,
lanatoside C,
medigoxin.

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12
= Corticosteroids: beclomethasone, betamethasone, budesonide, cortisone
acetate,
desoxymethasone, dexamethasone, fiudrocortisone acetate, flunisolide,
flucortolone,
fluticasone propionate, hydrocortisone, methylprednisolone, prednisolone,
prednisone, triamcinolone.
= Diuretics: acetazolamide, amiloride, bendrofluazide, bumetanide,
chlorothiazide,
chlorthalldone, ethacrynfc acid, frusemIde, metolazone, spironolactone,
triamterene.
= Anti-Parkinson agents: bromocriptine mesylate, lysuride maleate.
= Gastro-intestinal agents: bisacodyl, cimetidine, cisapride, dlphenoxylate
HCI,
domperidone, famotidine, loperamide, mesalazine, nizatidine, omeprazole,
ondansetron HCI, ranitidine HC), sulphasalazine.
= Histamine H1-receptor antagonists: acrivastine, astemizole, cinnarizine,
cyclizine,
cyproheptadine HCI, dimenhydrinate, flunarizine HCI, loratadine, meclozine
HCI,
oxatomide', terfenadine, triprolidine.
= Lipid regulating agents: bezafibrate, clofibrate, fenofibrate,
gemfibrozil, probucot.
= Local anaesthetics: Neuro-muscular agents: pyridostigmine.
= Nitrates and other anti-anginal agents: amyl nitrate, glyceryi
trinitrate, isosorbide
dinitrate, isosorbide mononitrate, pentaerythritol tetranitrate.
= Nutritional agents: betacarotene, vitamin A, vitamin B2, vitamin D,
vitamin E,
vitamin K.
= Opioid analgesics: codeine, dextropropyoxyphene, diamorphine,
dihydrocodeine,
meptazinol, methadone, morphine, nalbuphine, pentazocine, medazolam, fentanyl.
= Oral vaccines: Vaccines designed to prevent or reduce the symptoms of
diseases
of which the following is a representative however not exclusive list:
Influenza,
Tuberculosis, Meningitis, Hepatitis, Whooping Cough, Polio, Tetanus,
Diphtheria,
Malaria, Cholera, Herpes, Typhoid, HIV, AIDS, Measles, Lyme disease,
Travellers'
Diarrhea, Hepatitis A, B and C, Otitis Media, Dengue Fever, Rabies,
Parainfiuenza,
Rubella, Yellow Fever, Dysentery, Legionnaires Disease, Toxoplasmosls, Q-
Fever,
Haemorrhegic Fever, Argentina Haemorrhagic Fever, Caries, Chagas Disease,
Urinary Tract Infection caused by E. coli, Pneurnoccoccal Disease, Mumps, and
Chikungunya.

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13
= Vaccines to prevent or reduce the symptoms of other disease syndromes of
which the
follow4no is a representative, however not exclusive list of causative
organisms:
Vibrio species, Salmonella species, Bordetella species, Haemophilus species,
Toxoplasmosis gondii, Cytomegalovirus, Chiamydia species, Streptococcal
species,
Norwalk Virus, Escherischia coil, Helicobacter pylori, Rotayirus, Neisseria
gonorrhae,
Neisseria meningiditis, Adenovirus, Epstein Barr Virus, Japanese Encephalitis
Virus,
Pneumocystis carini, Herpes simplex, Clostridia species, Respiratory Syncytial
Virus,
Klebsielia species, Shigella species, Pseudomonas aeruglnosa, Parvovirus,
Campylobacter species, Rickettsia species, Varicella zoster, Yersinia species,
Ross
River Virus, J. C. Virus, Rhodococcus egui, Meraxella catarrhalis, Borrelia
burgdorferi
and Pasteurella haemolytica. Further specific examples include opioids such as
fentanyl or midazolam.
= Vaccines directed to non-infections immune-modulated disease conditions:
such as
topical and systematic allergic conditions such as Hayfever, Asthma,
Rheumatoid
Arthritis and Carcinomas.
= Vaccines for veterinary use: including those directed to Coccidiosis,
Newcastle
Disease, Enzootic pneumonia, Feline leukaemia, Atrophic rhinitis, Erysipelas.
Foot
and Wirth disease, Swine, pneumonia, and other disease conditions and other
infections and auto-immune disease conditions affecting companion and farm
animals.
= Proteins. peptides and recombinant drugs: insulin
(hexameric/dimerictmonommic
forms), glucagon, growth hormone (somatotropin), polypeptides or their
derivatives,
(preferably with a molecular weight from 1000 to 300,000), calcitonins and
synthetic
modifications thereof, enkephalins, interferons (especially Alpha-2 interferon
for
treatment of common colds), LHRH and analogues (nafarelin, buserelin,
zolidex),GHRH (growth hormone releasing hormone), secretin, bradykin
antagonists,
= GRF (growth releasing factor), THF, TRH (thyrotropin releasing hormone),
ACTH
analogues, 1GF (insulin like growth factors), CGRP (calcitonin gene related
peptide),
atrial natriurectic peptide, vasopressin and analogues (DDAVP, lypressin),
factorVIII,
G-GSF (granulocyte-colony stimulating factor), EPO (erythropoltin).
= Sex hormones: clomiphene citrate,
danazol, ethinyloestradiol,
medroxyprogesterone acetate. mestranol, methyltestosterene, norethisterone,
= norgestrel, oestradiol, conjugated oestrogens, progesterone, stanozolol,
stiboestrol,
testosterone, tibolone.

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14
= Spermicides: nonoxynol 9.
= Stimulants: amphetamine, dexamphetamine, dexfenfluramine, fenfluramine,
mazindol, pemoline.
[00042]
Notwithstanding the general applicability of the method of the invention, more
specific examples of biologically active materials include, but are not
limited to: halopericlol
(dopamine antagonist), DL isoproterenol hydrochloride (13-adrenergic agonist),
terfenadine
(Hi -antagonist), propranolol hydrochloride ([3-adrenergic antagonist),
desipramine
hydrochloride (antidepressant), &Menet', citrate, tadalafil and vardenafii.
Minor analgesics
(cyclooxygenase Inhibitors), fenamic acids, piroxicam, Cox-2 inhibitors,
naproxen, and
others, may all benefit from being formulated into an oral dosage form of the
present
invention.
[00043] Further
examples of biologically active materials include, but are not limited to:
alfaxalone, acetyl digoxin, acyclovir analogs, alprostadil, aminofostin,
anipamil, antithrombin
atenold, azidothymidine. beclobrate, beclomethasone, beMmycin, benzocaine and
derivatives, beta carotene, beta endorphin, beta interferon, bezafibrate,
binovum, biperiden,
bromazepam, bromocryptine, bucindolol, buflomedll, bupivacaine, busulfan,
cadralazine,
camptothesin, canthaxanthin, captopril, carbamazepine, carboprost, cefalexin,
cefalotin.
cefamandole, cefazedone, cefiuoroxime, cefinenoxime, cefoperazone, cefotaxime,
cefoxitin,
cefsulodin, ceftizoxime, chlorambucil, chromoglycinic acid, ciclonicate,
ciglitazone, clonidlne,
cortexolone, corticosterone, cortisol, cortisone, cyclophosphamide,
cyclosporin A and other
cyclosporins, cytarabine, desocryptin, desogestrel, dexamethasone esters such
as the
acetate, dezocine, diazepam, didofenac, dideoxyadenoslne, dideoxyinosine,
digitoxin,
digoxin, dihydroergotamine, dihydroergotoxin, diltiazem, dopamine antagonists,
doxorubicin,
econazole, endralazine, enkephalin, enalapril, epoprostenol, estradiol,
estramustine,
etofibrate, etoposide, factor ix, factor viii, felbamate, fenbendazole,
fenofibrate, fexofenedine,
flunarizin, flurbiprofen, 5-fluorouracil, fiurazepam, fosfomycin,
fosmidomycin, furosemide, =
gallopamil, gamma interferon, gentamicin, gepefrine, gliciazide, glipizide,
griseofulvin,
haptoglobulin, hepatitis B vaccine, hydralazine, hydrochlorothiazide,
hydrocortisone,
ibuprofen, ibuproxam, indinavir, indomethacin, iodinated aromatic x-ray
contrast agents such
as iodamide, ipratropium bromide, ketoconazole, ketoprofen, ketotifen,
ketotifen fumarate, K-
strophanthin, labetalol, lactobacillus vaccine, lidocaine, Ildoflazin,
lisuride, lisuride hydrogen
maleate, lorazepam, lovastatin, mefenamic acid, melphalan, memantin,
mesulergin,
metergoline, methotrexate, methyl digoxin, methylprednisolone, metronidazole,
metisoprenol, metiprandol, metkephamide, metolazone, metoprolol, metoprolol
tartrate,
miconazole, miconazole nitrate, mlnoxidil, misonidazol, moisidomin, nadolol,
nafiverine,

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nafazatrom, naproxen, natural insulins, nesapidil, nicardipine, nicorandil,
nifedipine, niludipin,
nimoctipine, nitrazepam, nitrendipine, nitrocamptothesin, 9-nitrocamptothesin,
olanzapine,
oxazepam, oxprenolol, oxytetracycline, penicillins such as penicillin G
benethamine,
penecillin 0, phenyibutazone, picotamide, pindoloi, piposulfan, piretanide,
piribedil,
piroxicam, pirprofen, plasminogenici activator, prednlsolone, prednisone,
pregnenolone,
procarbacin, procaterol, progesterone, proinsulln, propafenone, propanolol,
propentofyilin,
propofol, propranolol, raloxifene, rifapentin, simvastatin. semi-synthetic
Insulins, sobrerol,
somastotine and its derivatives, somatropin, stilamine, suifinalol
hydrochloride,
sulfinpyrazone, suloctidil, suprofen, sulproston, synthetic insulins,
talinolol, taxol, taxotere,
testosterone, testosterone propionate, testosterone undecanoate, tetracane HI,
tlaramide
HCI, tolmetin, tranilast, triquilar, tromantadine HC1, urokinase, valium,
verapamil, vidarabine,
vidarabine phosphate sodium salt, vinblastine, vinburin, vincamine,
vincristine, vindesine,
vinpocetine, vitamin A, vitamin E succinate, and X-ray contrast agents.
[00044] In addition, it Is also expected that new chemical entities (NCE)
and other actives
for which the solid dosage forms of the present invention are suitable for
delivery of will be
created or become commercially available in the future and can be used as the
biologically
active material.
The biological active material may be an active material that binds to one or
more adrenergic
receptors. Preferably, the active material that binds to one or more
adrenergic receptors is
adrenaline (epinephrine), or an adrenaline salt, such as adrenaline bitartrate
or adrenaline ,
hydrochloride. Alternatively, the active material that binds to one or more
adrenergic
receptors may be provided in the form of analogues and compounds related to
adrenaline,
such as norepinephrine, isoprenaline; or symphatomimetic agents such as
tyramine,
ephedrine, pseudoephedrine, the amphetamines, salbutamol, and terbutallne.
[00045] The biologically active material may be an N-methyl-D-aspartate
receptor
antagonist. Preferably, the N-methyl-D-aspartate receptor antagonist is chosen
from the list
comprising: dextromethorphan, dextrorphan or ketamine.
[00046] The biologically active material may be a cyclic guanosine
monophosphate =
(cGMP) phosphodiesterase type 5 (PDE5) inhibitor. Preferably, the cyclic
guanosine
monophosphate (cGMP) phosphodiesterase type 5 (PDE5) inhibitor is sildenafil
or a
pharmaceutically acceptable salt thereof. Preferably, the sildenafil salt Is
sildenafil citrate.
[00047] Preferably, the solid dosage form Is a form selected from the group
consisting of:
a wafer; tablet; capsule; pill; powder; pellet; granule; and film The solid
dosage form should
be adapted to not leave a residue of said dosage form in the oral cavity that
Is detectable by

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16
the patient. Whichever form the solid dosage form is provided in; it should
quickly
disintegrate in the oral cavity, and allow the rapidly dissolving biologically
active material to
be absorbed by diffusion through the oral mucosa and directly into the
systemic blood
circulation system. Preferably, the solid dosage form is a fast dissolving
solid dosage form.
= Constituents
[00048] Preferably,
the solid dosage form is substantially free of starch. In a further
embodiment of the invention a pharmaceutical composition comprising the solid
dosage form
is also substantially free of starch. Preferably, the solid dosage form is a
fast dissolving solid
dosage form.
[00049] The precise
quantity of biologically active material in the solid dosage form will
depend on the type of biologically active material selected. However, the
active material is
generally present in an amount from 0.02 to 95%, preferably 0.02 to 20% or
preferably 0.1 to
75%, Ito 46% by dry weight of the dosage form.
[00050] The
biologically active material may be generally present in the solid dosage
form in an amount selected from the group consisting of: 5mg; 10mg; 15mg;
20mg; 25mg;
30mg; 35mg, 40mg, 45mg, 50 mg, 60mg and 100mg.
[00051] Preferably,
the solid dosage form of the present invention also comprises at least
one matrix forming agent.
[00052] In the
freeze-dried systems of the prior art, gelatine is the most commonly used
carrier or structure forming agent due to its wall-forming ability. Gelatine
is a water soluble
polymer, and as such, when mixed with active pharmaceutical ingredients in
water; the
increasing viscosity of the solution over time may cause a decreasing
solubility of poorly
soluble drugs in the mixture, and lead to a ,suspension of the drug in
gelatine matrix. This
can cause phase separation to occur; and the drug in amorphous or crystalline
forms may
not be homogenously dispersed in the matrix, which will eventually affect the
dissolution and
absorption of the final product. Therefore, preferably gelatine is not present
in the solid
dosage form of the present invention.
[00053] The
effectiveness of the solid dosage form of the present invention relies on the
biologically active material dissolving in a small volume of fluid, such as in
the oral cavity,
prior to absorption into the systemic circulation. Therefore, the rate of
dissolution of the
dosage form is important. In a preferred embodiment of the present invention,
the solid
dosage form comprises a super-disintegrant as at least one matrix forming
material.

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[00054] Other
polymer materials suitable for forming a matrix may be selected for
specific application in the solid dosage form, especially for site-specific
drug delivery system
such as in the oral cavity. Matrix forming agents of the present invention may
be selected
from the group consisting of: non-mammalian gelatine, dextrin, soy protein,
wheat protein,
psyllium seed protein, acacia gum, guar gum, agar gum, xanthin gum,
polysaccharides:
alginates; sodium carboxymethylcellulose; carrageenans; dextrans; pectins;
sugars; amino
acids; starch; modified starches; carboxymethylcellulose;
hydroxypropylmethylcellulose;
hydroxypropyl cellulose and methyl cellulose Inorganic salts; synthetic
polymers;
amylopectin, potypeptidetprotein or poly-saccharide complexes.
[00055) The matrix
forming material in the solid dosage form may be a carbohydrate.
Preferably, the carbohydrate is selected from the group consisting of:
mannitol; dextrose;
lactose; galactose; trehalose; and cyclodextrin.
[00056) In a highly
preferred embodiment, at least one matrix forming agent in the solid
dosage form is glycine. %eine is = an amino acid with excellent wetting
properties and is
suitable for the fast dissolving formulation. Low amounts of glycine may be
used in the
formulation of the present invention to control the dissolution rate of the
dosage form.
Furthermore, glycine may also be used as an anti-collapsing agent, which
maintains the
dosage form from shrinking either during the manufacture process or after
packing. In one
embodiment, the glycine is present in the dosage form of the present invention
in an amount
from 0.2 to 7.5%, more preferably from about 0.5% to about 5% dry weight of
the dosage
form. Preferably, the glycine is present in an amount from 0.5 to 5 weight %
by dry weight of
the composition of the dosage form.
[00057) In a highly
preferred embodiment, at least one matrix forming agent in the solid
dosage form Is sodium carboxymethylcellulose. When at least one matrix forming
agent is
sodium carboxymethylcellulose, the polymer is present in a concentration of
from about
0.1% to about 19% by dry weight of the solid dosage form. In a preferred
embodiment the
sodium carboxymethylcellulose is present in an amount of about 0.1% to about
15% by dry
weight of the dosage form. In a highly preferred embodiment of the present
Invention, the
sodium carboxymethylcellulose is present in an amount of about 0.1% to about
1.0% by dry
weight of the solid dosage form. Preferably, the sodium carboxymethylcellulose
is present in
an amount by dry weight of the composition of the dosage form selected from
the group
consisting of: 0.05% to 19%; 0.1% to 15%; and 0.1% to 10%.
[00058] In another
embodiment of the present Invention, the dosage form comprises
amylopectin as at least one matrix forming agent. Amylopectin is capable of
increasing the
release of the biologically active agent by promoting formulation
disintegration. Amylopectin
,

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18
may be present in the dosage form at a concentration about 2% up to no great
than 20% by
dry weight of the solid dosage form. Amylopectin may be present in an amount
of about 2%
to about 17% dry weight of the dosage form. Preferably, amylopectin is present
in an amount
by dry weight of the composition of the dosage form selected from the group
consisting of:
2% to 17%; and 2% to 15%.
[00059] According to another embodiment of the invention, the solid dosage
form may
include a matrix forming agent such as mannitol. Mannitol is a component that
may aid in
the crystalline structure and impart hardness of the dosage form. When
mannitol is present
in the dosage form, it occurs In a concentration of from about 6% to about
80%, preferably
from about 10% to about 60%, and most preferably from about 10% to about 50%
by dry
weight of the dosage form.
[00060] The solid
dosage form may contain an inorganic salt. Preferably, the inorganic
salt is selected from the group consisting of: sodium phosphate; sodium
chloride; and
aluminium silicates.
[00061] The solid
dosage form of the invention may contain an amino acid. Preferably,
the amino acid is selected from the group consisting of: glycine; L-alanine; L-
aspartic acid; L-
glutamic acid; L-hydroxyproline; L-isoleucine; L-leucine; and L-phenylalanine.
[00062] The solid
dosage form of the invention may also preferably be substantially free
of starch,
[00063] To achieve a
rapid dissolution of biologically active materials from the solid
dosage form of the invention, diluents may be added as at least one matrix
forming material.
Diluents include microcrystalline cellulose (e.g., Avicel PH 101 and Avice)
PH 102m,
lactose, starch and sorbitol. These diluents may be present in the dosage form
either alone
or as a mixture in different ratios, and may be about 1% to about 80%,
preferably about 2%
to about 50%, either individually or cumulatively.
[00064] In one
embodiment of the present invention, the solid dosage form comprises
microcrystalline cellulose as the at least one matriX forming agent.
Microcrystalline cellulose
may act as a filler and binder In the dosage form of the present invention.
Microcrystalline
cellulose has the ability to compact with minimum compression pressures, and
results in a
hard, stable dosage form, preferably one that is fast dissolving. Due to its
large surface area
and high internal porosity, microcrystalline cellulose Is able to absorb and
retain large
amounts of water, which is desirable in the dosage form of the invention. When
the solid
dosage form of the present invention comprises microcrystalline cellulose, it
is present in an

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19
amount of about 1% to about 10%, and preferably from about 1% to about 8% by
dry weight
of the dosage form.
100065] The
solid dosage form or the pharmaceutical composition of the invention may
preferably be substantially free of Avicel.
[00066] In
another preferred embodiment, the solid dosage form comprises at least one
lubricant. The dosage form of the present invention may include lubricants
such as
polyethylene glycol (PEG) 1000, 2000, 4000 and 6000, sodium lauryl sulphate,
fats or oils.
One advantage of the use of these lubricants is to aid in the removal of the
dosage form
from the mould. These lubricants may be present in the dosage form either
alone or as a
mixture in different ratios, and may be between 0.05% to 5%, preferable
between 0.1% and
2%, preferable about 1.5%, either Individually or cumulatively.. In one
embodiment, the
composition includes between 0.05% to 5% polyethylene glycol 2000, preferably
between
0.1% and 2% polyethylene glycol 2000, preferably about 1.5% polyethylene
glycol 2000 by
dry weight of the dosage form, or as mixtures of the various glycols.
Alternatively, the PEG
2000 can be replaced by PEG 1000.
[00067] In
another preferred embodiment, the solid dosage form comprises at least one
buffer reagent. Preferably, the buffer reagent in the solid dosage form
provides a saliva pH
of 7.0 to 7.8 when dissolved in the oral cavity. Such buffer reagents may
Improve the
sublingual absorption of weak base compounds. The solid buffer reagent may be
selected
from the group comprising: sodium dihydrogen phosphate dehydrate, sodium
hydrogen
phosphate, sodium hydrogen carbonate and sodium carbonate, which may be
present in the
dosage form either alone or as a mixture in different ratios in a
concentration of about 0.01%
to about 10% by weight of the composition.
[00068]
Alternatively, the solid buffer reagent may be chosen from the list
comprising:
alginic acid, ascorbic acid, citric acid, malic acid, succinIc acid and
tartaric acid, which may
- be present in the dosage form either alone or as a mixture in
different ratios in a concentration
of about 0.01% to about 10% by weight of the composition. Preferably, the
buffer reagent is
citric acid, which may be present in a concentration of about 0.01% to about
10% by weight of
the solid dosage form, more preferably between 0.1% and 5%, most preferably
about 2.0%.
[00069] For
example, if the biologically active material In the solid dosage form is
sildenafil, the molecular structure of sildenafil has both weakly acid centre
and weakly basic
centre. It means sildenafil solubility in water is affected by the solution pH
value and the two
optimum pH (pHmax) values are 4.5 and 10.24. Therefore, to improve
transmucosal
absorption of sildenafil, the solid dosage form may comprise a solid buffer
reagent that

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produces a saliva pH of 5.0 to 6.0 when dissolved in oral cavity. Increasing
the pH of the
solution of sildenahl can decrease the ratio of unionized to ionized
particles. which will lead
to enhanced transmucosal absorption.
[00070] Preferably,
the buffer reagent is sodium carbonate, which may be present in a
concentration of about 0.01% to about 10% by weight of the solid dosage form,
more
preferably between 0.1% to 1%, most preferably about 0.3% or 0.5% of the solid
dosage
form.
[00071] The solid
dosage form may, in certain embodiments, include at least one
absorption enhancer. The absorption enhancer may be a polysaccharide and may
be
positively charged. Preferably, the absorption enhancer is 8-cyclodextrin or
its derivatives.
The p-cyclodextrin or derivative may be present in a concentration of from
about 0.01% to
about 10% by dry weight of the dosage form, preferably between 0..2% to 2%,
and most
preferably about 1%. Alternatively, the at least one absorption enhancer may
comprise
glyceryl trinitrate (also known as GTN or nitroglycerin) or a derivative
thereof. The glyceryl
trinitrate or derivative may be present In a concentration of from about 0.01%
to about 20%
by dry weight of the dosage form, more preferably between 0.2% to 4%, and most
preferably
about 2%.
[00072] The solid
dosage form of the present invention may comprise flocculating agents
to maintain even disbursement of the biologically active material in the
matrix during the
manufacture process. The flocculating agent may be gums. Preferable, the gum
is xanthan
gum. The Xanthan gum may be present in a concentration of about 0.01% to about
10% by
dry weight of the solid dosage form, preferably from about 0.2% to 2%, and
most preferably
about 1%.
[00073] In another
preferred embodiment, the solid dosage form comprises at least one
surfactant. To aid dissolution of the biologically active material into an
aqueous environment
such as the oral cavity, a surfactant may be added to the solution as a
wetting agent.
Suitable surfactants include anionic detergents such as sodium lauryl sulfate,
dloctyl sodium
sulfosuccinate and dloctyl sodium suffonate. Cationic detergents may be used
and include
benzalkonium chloride or benzethomium chloride. The list of possible non-ionic
detergents
includes lauromacrogol 400, polyoxyl 40 stearate, polyoxyethylene hydrogenated
castor oil
10, 60 and 60, glycerol monostearate, polysorbate 40. 60, 65 and 80, sucrose
fatty acid
ester, methyl cellulose and carboxymethyl cellulose. These surfactants may be
present in
the dosage form either alone or as a mixture in different ratios. Preferably,
the surfactant
aids in creating a fast dissolving solid dosage form.

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21
[00074] Additives
which potentially enhance uptake of the biologically active materials
may also be present in the solid dosage form. Such additives may be selected
from the list
comprising: fatty acids such as oleic acid, linoleic acid and lindenic acid.
[00075] In order
to enhance the aesthetic and taste appeal of the solid dosage form to
the subject, the dosage form may also contain at least one additive, such as a
colouring
agent or flavouring agent. The colouring agent may preferably be FD&C dyes
Blue No. 2
and Red No. 40; the flavouring agent may be chosen from the list comprising:
orange, mint,
raspberry and caramel, and/or sweeteners such as aspartame and saccharin, or a
mixture of
two or more flavouring agents.
[00076] Thus, in a
highly preferred embodiment, the present invention provides a solid
dosage form adapted for the release of a biologically active material in the
oral cavity
wherein the dosage form comprises:
(a) at least one biologically active material and
(b) at least one matrix forming agent,
= wherein the dosage form substantially dissolves in the oral cavity;
wherein the dosage form
comprises "0.29% sodium carbonate, 0.59% sodium carboxymethylcellulose, 1.48%
PEG
2000, 2.97% glyoine, 5.93% microcrystalline cellulose; 14.84% amylopectin,
29.67% lactose
and 44.23% mannitol as a dry weight of the solid dosage form; and which does
not result in
substantial detectable levels of residue left over in the oral cavity of the
patient. Preferably,
the solid dosage form is a fast dissolving solid dosage form. PEG 2000 could
be replaced
with PEG 1000 with the same advantages as the oral dosage form described
above.
[00077)
Preferably, the biologically active material in the solid dosage form of the
present
invention is chosen from the list comprising: at least one cyclic guanosine
monophosphate
(cGMP) phosphodiesterase type 5 (PDE5) inhibitor, an active"material that
binds to one or
more adrenergic receptors, and an N-methyl-D-aspartate receptor antagonist.
Preferably,
the N-methyl-D-aspartate receptor antagonist is chosen from the list
comprising:
dextromethorphan, dextrorphan or ketamine. Preferably, the active material
that binds to
one or more adrenergic receptors is adrenaline, or an adrenaline salt.
Preferably, the cyclic
guanosine monophosphate (cOMP) phosphodiesterase type 5 (PDE5) inhibitor is
sildenafil
or a pharmaceutically acceptable salt thereof. Preferably, the sildenafil salt
is sildenafil
citrate.
= Carriers and Excipients
=

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22
[00078] As discussed
above, the solid dosage forms of the present invention may include
one or more pharmaceutically acceptable carriers. The use of such
pharmaceutically
acceptable carriers for the manufacture of medicaments such as solid dosage
forms,
including fast dissolving solid dosage forms, is well known in the art. Except
insofar as any
conventional pharmaceutically acceptable carrier is incompatible with the
biologically active
material, use thereof in the manufacture of a solid dosage form according to
the invention is
=
contemplated.
[00079]
Pharmaceutical acceptable carriers according to the invention may include one
or more of the following examples:
(1) surfactants and polymers, including, however not limited to
polyethylene glycol (PEG),
polyvinylpyrrolid one, polyvinylalcohol, crospovid
one, polyvinylpyrrolid one-
polyvinyiacrylate copolymer, cellulose derivatives, hydroxwropylmethyl
cellulose,
hydroxypropyl cellulose, carboxyrriethylethyl cellulose, hydroxypropylmethyl
cellulose
phthalate, polyacrylates and polymethacrylates, urea, sugars, polyols, and
their
polymers, emulsifiers, sugar gum, starch, organic acids and their salts, vinyl
pyrrolidone and vinyl acetate; and/or
(2) binding agents such as various cellu loses and cross-linked
polyvinylpyrrolidone,
microcrystalline cellulose; and/or
(3) filling agents such as lactose monohydrate, lactose anhydrous, mannitol,
microcrystalline cellulose and various starches; and/or
(4) lubricating agents such as agents that act on the flowability of the
powder to be
compressed, including colloidal silicon dioxide, talc, stearic acid, magnesium
stearate,
calcium stearate, silica gel; and/or
(5) sweeteners such as any natural or artificial sweetener including sucrose,
xylitol,
sodium saccharin, cyclamate, aspartame, and ac,csulfame K; and/or
(6)` flavouring agents; and/or .. = .
(7) preservatives such as potassium sorbate, methylparaben, propylparaben,
benzoic acid
and its salts, other esters of parahydroxybenzoic acid such as butylparaben,
alcohols
such as ethyl or benzyl alcohol, phenolic chemicals such as phenol, or
quartemary
compounds such as benzalkonlum chloride; antioxidants such as ascorbic acid,
potassium sorbate, sodium bisulfate sodium metabisulfite and sorblc acid;
and/or
(8) buffers; and/or

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23
(9) diluents such as pharmaceutically acceptable inert fillers, such as
microcrystalline
cellulose, lactose, dibasic calcium phosphate, saccharides, and/or mixtures of
any of
the foregoing; and/or
(10) wetting agents such as corn starch, potato starch, maize starch, and
modified
starches, croscarmellose sodium, crosspovidone, sodium starch giycolate, and
mixtures thereof; and/or
(11) disintegrants; and/or
(12) effervescent agents such as effervescent couples such as an organic acid
(0.9,, citric,
tartaric, malic, fumaric, adipic, succinic, and alginic acids and anhydrides
and acid
salts), or a carbonate (e.g. sodium carbonate, potassium carbonate, magnesium
carbonate, sodium glycine carbonate, L-lysine carbonate, and arginine
carbonate) or
bicarbonate (e.g. sodium bicarbonate or potassium bicarbonate);
(13) absorption enhancer such as glyceryl trinitrate; and/or
(14) other pharmaceutically acceptable excipients,
[00080] in another
embodiment, more than one biologically active material may be
combined into the solid dosage form of the present invention. In one example,
if the
biologically active material is adrenaline, a fast dissolving solid dosage
form may be
achieved which provides for different release characteristics ¨ early release
from adrenaline,
arid later release from a larger average size adrenaline.
[00081] Solid dosage
forms of the invention suitable for use in animals, and in particular
in human beings, typically must be sterile and stable under the conditions of
manufacture
and storage. The solid dosage forms of the invention comprising the
biologically active
material can be formulated as a solid, a liposome, or other ordered structures
suitable to
high drug concentration adapted for oral delivery.
[00082) Actual
dosage strengths of the biologically active material in the solid dosage
form of the invention may be varied in accordance with the nature of the
biologically active
material, as well as the potential increased efficacy due to the advantages of
providing and
administering the biologically active material. Thus as used herein
"therapeutically effective
amounr will refer to an amount of biologically active material required to
effect a therapeutic
response in a subject. Amounts effective for such a use will depend on; the
desired
therapeutic effect; the Potency of the biologically active material; the
desired duration of
treatment; the stage and severity of the disease being treated; the weight and
general state
of health of the patient; and the judgment of the prescribing physician.

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[00083] For example,
If adrenaline is the biologically active material in the solid dosage
form of the invention, the actual dosage strengths of the adrenaline may be
varied in
accordance the nature of the anti-allergic/anti-anaphylaxis, as well as the
potential increased
efficacy due to the advantages of providing and administering the
antiallergic.
[00084] The solid
dosage forms of the Invention are orally administered to a subject.
Solid dosage forms for oral administration include wafers, capsules, tablets,
pills, powders,
pellets, films and granules. Preferably, the solid dosage form is administered
sub-lingually.
Preferably, the solid dosage form is a fast dissolving solid dosage form.
100085)
Incorporating any of the normally employed excipients, such as those
previously
listed, and generally 0.1% to 95% of the biologically active material, and
more preferably
0.1% to 75% of the material, will form a pharmaceutically acceptable non-toxic
solid dosage
form for oral administration.
[00088] Although the
solid dosage form of the present invention may be administered as a
wafer, tablet, capsule; pill; powder; pellet; granule; or film, the oral
dosage form of the present
invention is also suitable for use with a nebulizer, either jet or ultrasonic,
and will typically
comprise the solid dosage form suspended in water. The dosage form of the
present invention
may also include a buffer and a simple sugar (e.g., for protein stabilization
and regulation of
osmotic pressure). The nebulizer formulation may also contain a surfactant, to
reduce or
prevent surface induced aggregation of the compounds caused by atomization of
the solution in
forming the aerosol. Preferably, the solid dosage form is a fast dissolving
solid dosage form.
[00087] The
nebulized solid dosage form should preferably not leave a residue of said
dosage form In the oral cavity that Is detectable by the patient. The rapidly
dissolving
biologically active material in the nebulized dosage form should quickly be
absorbed by
diffusion through the oral mucosa and directly into the systemic blood
circulation system.
[00088] According to
another aspect of the present invention, there Is provided a solid
dosage form adapted for the release of an active material that binds to one or
more
adrenergic receptors in the oral cavity wherein the dosage form comprises:
(a) an active material that binds to one or more adrenergic receptors, and
=
(b) at least one matrix forming agent,
wherein the dosage form substantially dissolves in the oral cavity.
Preferably, the solid
dosage form is a fast dissolving solid dosage form. Preferably, the active
material that binds
to one or more adrenergic receptors is adrenaline, or an adrenaline salt.
Alternatively, the
adrenaline may be provided in the form of analogs and compounds related to
adrenaline,

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such as norepinephrine, isoprenaline; or symphatomimetic agents such as
tyramine,
ephedrine, pseudoephedrine, the amphetamines, salbutamol, and terbutaline,
[00089) In one embodiment, the active material that binds to one or more
adrenergic
receptors, such as adrenaline, is present in an amount by dry weight of the
solid dosage
form selected from the group consisting of: 0.01 to 95%; 0.1 to 75% and 1 to
45%.
[00090) In another embodiment, the dosage form comprises:
(a) 0,01 to 95 (dry) weight % of an active material that binds to one or more
adrenergic receptors;
(b) between 2 to 17% (dry) weight % of amylopectin;
(c) between 0.01 to 50) (dry) weight % of at least one matrix forming
agent;
(d) between 0.01 to 40 (dry) weight % of a filling agent;
(e) between 0.01 to 10 (dry) weight % of an amino acid; and-
(f) between 0.01 to 20 (dry) weight % of a glycol/surfactant
(g) between 0.01 to 60 (dry) weight % carbohydrate;
(h) between 0.1 to 1 (dry) weight % of a solid buffer reagent;
(i) between 0.01 to 20 (dry) weight % of a absorption enhancer
[00091] In a highly preferred embodiment, the present invention provides a
solid dosage
form adapted for the release of an active material that binds to one or more
adrenergic
receptors, such as adrenaline, in the oral cavity wherein the dosage form
comprises:
(a) an active material that binds to one or more adrenergic receptors; and
(b) at least one matrix forming agent,
wherein the dosage form substantially dissolves in the oral cavity, wherein
the dosage form
comprises 0.25% sodium carbonate, 0.50% sodium carboxymethylceliulose, 1.25%
PEG
2000, 2.49% glycine, 2.49% microcrystalline cellulose; 12.49% amylopectin,
24.98% lactose,
2.00% glyceryl trinitrate and 3746% mannitol as a dry weight of the solid
dosage form, and
which does not result in substantial detectable levels of residue left over in
the oral cavity of
the patient. Preferably, the solid dosage form is a fast dissolving solid
dosage form.
(00092] In another embodiment, the dosage form comprises a quantity of an
active
material that binds to one or more adrenergic receptors, such as adrenaline,
selected from

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the group consisting of: 5mg; 10mg; 15mg; 20mg; 25mg; 30mg: 35mg, 40mg, 45mg,
50 mg,
60mg and 100mg.
100093] According to another aspect of the present invention, there is
provided a solid
dosage form adapted for the release of at least one cyclic guanosine
monophosphate
(cGMP) phosphodiesterase type 5 (PDE5) inhibitor in the oral cavity wherein
the dosage
form comprises:
(a) at least one cyclic guanosine monophosphate (cGMP) phosphodiesterase type
5
(PDE5) inhibitor, and
(b) at least one matrix forming agent,
wherein the dosage form substantially dissolves in the oral cavity.
Preferably, the solid
dosage form is a fast dissolving solid dosage form. Preferably, the cyclic
guanosine
monophosphate (cGMP) phosphodiesterase type 5 (PDE5) inhibitor is sildenafil
or a
pharmaceutically acceptable salt thereof. Preferably, the sildenafil salt is
sildenafil citrate.
[00094] In one embodiment, the at least one cyclic guanosine monophosphate
(cGMP)
phosphodiesterase type 5 (PDE5) inhibitor is present in an amount by dry
weight of the solid
dosage form selected from the group consisting of: 0.01 to 95%; 0.1 to 75% and
Ito 45%.
100095] In another embodiment, the dosage form comprises:
(a) 0.01 to 95 (dry) weight % of at least one cyclic guanosine monophosphate
(cGMP) phosphodiesterase type 5 (PDE5) inhibitor;
(b) between 2 to 17% (dry) weight % of amylopectin;
(c) between 0.01 to 50) (dry) weight % of at least one matrix forming
agent;
(d) between 0.01 to 40 (dry) weight % of a filling agent;
(e) between 0.01 to 10 (dry) weight % of an amino acid; and
(f) between 0.01 to 20 (dry) weight % of a glycolfsurfactant
(g) between 0.01 to 60 (dry) weight % carbohydrate;
(h) between 0.110 1 (dry) weight % of a solid buffer reagent;
(i) between 0.01 to 20 (dry) weight % of a absorption enhancer
[00096] In a highly preferred embodiment, the present invention provides a
solid dosage
form adapted for the release of at least one cyclic guanosine monophosphate
(cGMP)

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phosphodiesterase type 5 (PDE5) inhibitor in the oral cavity wherein the
dosage form
comprises:
(a) at least one cyclic guanosine monophosphate (cGMP) phosphodlesterase type
5
(PDE5) inhibitor; and
(b) at least one matrix forming agent,
wherein the dosage form substantially dissolves in the oral cavity, wherein
the dosage form
comprises 0.29% sodium carbonate, 0.59% sodium carboxymethylcellulose, 1.48%
PEG
2000, 2.97% glycine, 5.93% microcrystalline cellulose; 14.84% amylopectin,
29.67% lactose,
and 44.23% mannitol as a dry weight of the solid dosage form, and which does
not result In
substantial detectable levels of residue left over in the oral cavity of the
patient. Preferably,
the solid dosage form is a fast dissolving solid dosage form.
[00097] In another
embodiment, the dosage form comprises a quantity of at least one
cyclic guanosine monophosphate (cGMP) phosphodiesterase type 6 (PDE5)
inhibitor
selected from the group consisting of: 5mg; 10mg; 15mg; 20mg; 25mg; 30mg;
35mg, 40mg,
45mg, 60 mg, 60mg and 100mg.
[00098] According to
another aspect of the present invention, there is provided a solid
dosage form adapted for the release of an N-methyl-D-aspartate receptor
antagonist In the
oral cavity wherein the dosage form comprises:
(a) an N-methyl-D-aspartate receptor antagonist, and
(b) at least one matrix forming agent,
wherein the dosage form substantially dissolves in the oral cavity,
Preferably, the solid
dosage form is a fast dissolving solid dosage form. Preferably, the N-methyl-D-
aspartate
receptor antagonist is chosen from the list comprising: dextromethorphan,
dextrorphan or
ketamine.
100099] In one
embodiment. the N-methyl-D-aspartate receptor antagonist is present in
an amount by dry weight of the solid dosage form selected from the group
consisting of: 0.01
to 95%; 0.1 to 75% and Ito 45%.
[000100] In another embodiment, the dosage form comprises:
(a) 0.01 to 95 (dry) weight % of an N-methyl-D-aspartate receptor
antagonist;
(b) between 2 to 17% (dry) weight % of amylopectin;
(c) between 0.01 to 50) (dry) weight % of at least one matrix forming
agent:

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(d) between 0.01 to 40 (dry) weight % of a filling agent;
(e) between 0.01 to 10 (dry) weight % of an amino acid; and
(f) between 0.01 to 20 (dry) weight % of a glycol/surfactant
(g) between 0.01 to 60 (dry) weight % carbohydrate;
(h) between 0.1 to 1 (dry) weight % of a solid buffer reagent;
(I) between 0.01 to 20 (dry) weight % of a absorption enhancer
[000101] In a highly preferred embodiment, the present invention provides a
solid dosage
form adapted for the release of an N-methyl-D-aspartate receptor antagonist in
the oral
cavity wherein the dosage form comprises:
(a) an N-methyl-D-aspartate receptor antagonist; and
(b) at least one matrix forming agent,
wherein the dosage form substantially dissolves in the oral cavity, wherein
the dosage form
comprises 0.25% sodium carbonate, 0.50% sodium carboxymethylcellulose, 1.25%
PEG
2000, 2.49% glyclne, 2.49% microcrystalline cellulose; 12.49% amylopectin,
24.98% lactose,
and 37.46% mannitol as a dry weight of the solid dosage form, and which does
not result in
substantial detectable levels of residue left over in the oral cavity of the
Patient. Preferably,
the solid dosage form is a fast dissolving solid dosage form.
[0001021 In another embodiment, the dosage form comprises an N-methyl-D-
aspartate
receptor antagonist selected from the group consisting of: 5mg; 10mg; 15mg;
20mg; 25mg;
30mg; 35mg, 40mg, 45mg, 50 mg, 60mg and 100mg.
[000103] In another embodiment, the solid dosage form provides reduced
burning,
Irritation and/or discomfort on administration and/or swallowing compared to
convention
dosage forms.
[000104] In another embodiment, the dosage form is adapted for delivery via
the oral
cavity mucosa and into the systemic blood circulation system.
10001051 According to another aspect of the present Invention there is
provided a wafer
comprising a solid dosage form adapted for the release of a biologically
active material In an
oral cavity. Preferably, the solid dosage form wafer is a fast dissolving
solid dosage form
wafer. Preferably, the biologically active material is chosen from the list
comprising: at least
one cyclic guanosine monophosphate (cGMP) phosphodiesterase type 5 (PDE5)
inhibitor,
an active material that binds to one or more adrenergic receptors and an N-
methyl-D-

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aspartate receptor antagonist. Preferably, the N-methyl-D-aspartate receptor
antagonist is
chosen from the list comprising: dextromethorphan, dextrorphan or ketamine.
Preferably, the
cyclic guanosine monophosphate (cOMP) phosphodiesterase type 5 (PDE5)
inhibitor is -
sildenafil or a pharmaceutically acceptable salt thereof. Preferably, the
sildenafil salt is
sildenafil citrate. Preferably, the active material that binds to one or more
adrenergic
receptors is adrenaline, or an adrenaline salt. The wafer may be accompanied
by
instructions for its use.
[000106] Preferably, the solid dosage form wafer substantially dissolves once
placed in
the oral cavity in a time period selected from the group consisting of: less
than 2 minutes,
less than 1 minute, less than 50 seconds, less than 40 seconds, less than 30
seconds, less
than 20 seconds, less than 15 seconds, less than 10 seconds, less than 7.5
seconds, less
than 5 seconds, less than 4 seconds, less than 3 seconds, less than 2 seconds
after
administration of the dosage form. Preferably, the solid dosage form wafer is
a fast
dissolving solid dosage form wafer.
[000107] More preferably, the solid dosage form wafer completely dissolves
once placed
- in the oral cavity in a time period selected from the group consisting of:
less than 2 minutes;
less than 1 minute; less than 50 seconds; less than 40 seconds; less than 30
seconds; less
than 20 seconds; less than 15 seconds; less than 10 seconds; less than 7.5
seconds; less
than 5 seconds; less than 4 seconds; less than 3 seconds; and less than 2
seconds after
administration of the dosage form. Preferably, the solid dosage form wafer is
a fast
dissolving solid dosage form wafer.
Further features of the Invention provide for a solid dosage form wafer
according to the
Invention, wherein said dosage form substantially dissolves in the oral cavity
without leaving
a residue of said dosage form in the oral, cavity that Is detectable by a
subject. Preferably,
the solid dosage form wafer completely dissolves after oral, preferably
sublingual,
administration to the patient. As such, the subject has no urge to swallow the
wafer dosage
form and thus the biologically active material bypasses the gastrointestinal
tract and the
hepatic first-pass effect and is absorbed directly into the systemically
circulating blood.
Preferably, the solid dosage form wafer is a fast dissolving solid dosage form
Wafer.
Pharmaceutical Composition
[000108] The present invention also provides a pharmaceutical composition
comprising
the solid dosage form of the invention. Preferably, the solid dosage form is a
fast dissolving
solid dosage form.

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=
[000109] The pharmaceutical composition of the present invention can be
formulated to
additionally contain conventional additives or supplementary ,ingredients in
the usual
amounts of such materials. The composition can be in the form of a solid, a
liposome, or
other ordered structures suitable to high drug concentration adapted for oral
delivery.
Preferably the pharmaceutical composition is formulated to dissolve rapidly in
the oral
environment.
[000110] The composition may, in one embodiment, be formulated to be
substantially free
of preservatives, physiological or mucosa, absorption enhancers, or
propellants. The
composition may, in an alternative embodiment, be formulated to contain
preservatives,
physiological or mucosal absorption enhancers, or propellants.
Method
[000111] According to a further aspect of the present invention, there is
provided a method
to produce the solid dosage form of the present Invention comprising the steps
of:
a)combining at least one matrix forming agent with a biologically active
material to form a
mixture; and
b)freeze drying the mixture to form the solid dosage form.
Preferably, the solid dosage form is a fast dissolving solid dosage form.
[000112] There is also provided a method of producing the solid dosage form of
the
invention, comprising the steps of:
a)combining at least one matrix forming agent with an active material that
binds to one or
more adrenergic receptors to form a homogeneous mixture; and
b)freeze drying the mixture to form the solid dosage form.
Preferably, the solid dosage form is a fast dissolving solid dosage form.
[000113] There is also provided a method of producing the solid dosage form of
the
invention, comprising the steps of:
a)combining at least one matrix forming agent with at least one cyclic
guanosine
monophosphate (cGMP) phosphodiesterase type 5 (PDE5) inhibitor to form a
homogeneous mixture; and
b)freeze drying the mixture to form the solid dosage form.
c) Preferably, the solid dosage form is a fast dissolving solid dosage form.

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[000114] There is also provided a method of producing the solid dosage form of
the
invention, comprising the steps of:
a)combining at least one matrix forming agent with an N-methyl-D-aspartate
receptor
antagonist to form a homogeneous mixture; and
b)freeze drying the mixture to form the solid dosage form.
Preferably, the solid dosage form Is a fast dissolving solid dosage form.
[000116] Preferably, the method provides an oral solid dosage form wherein
said dosage
form substantially dissolves in the oral cavity without leaving a residue of
said dosage form
in the oral cavity that is detectable by a subject. Preferably, the solid
dosage form is a fast
dissolving solid dosage form.
[000116) Preferably, the method according to the invention produces a
soliddosage form
which substantially dissolves once placed in the oral cavity In a time period
selected from the
group consisting of: less than 2 minutes, less than 1 minute, less than 50
seconds, less than
40 seconds, less than 30 seconds, less than 20 seconds, less than 15 seconds,
less than 10
seconds, less than 7.5 seconds, less than 5 seconds, less than 4 seconds, less
than 3
seconds, less than 2 seconds after administration.
[000117] More preferably, the solid dosage form completely dissolves once
placed in the
oral cavity in a lime period selected from the group consisting of; less than
2 minutes; less
than 1 minute; less than 50 seconds; less than 40 seconds; less than 30
seconds; less than
20 seconds; less than 16 seconds; less thah 10 seconds; less than 7.5 seconds;
less than 6
seconds; less than 4 seconds; less than 3 seconds; and less than 2 seconds
after
administration of the dosage form.
[000118] In a preferred embodiment of the present Invention, the mixture
comprising the
matrix forming agent and the biologically active material is measured (by
weight or volume)
into a preformed plastic or aluminium blister mould (individual dose). The
blister mould is
placed into a freeze dryer for 24 hours and the resultant fast dissolving
solid dosage form is
then sealed with aluminium Of plastics foil to prevent moisture absorption.
Preferably, the
freeze drying technique is used to remove the solvent from the blister mould.
Sealing the
solid dosage form into the plastic or aluminium foil prevents or reduces
moisture absorption.
[000119] Preferably, the method of the present invention forms a solid dosage
form that is
a wafer. Preferably, the solid dosage form wafer is a fast dissolving solid
dosage form wafer.

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[000120] In one embodiment of the present invention, the method may require
that the pH
of the mixture Is adjusted to a pH within the range of between 3.0 and 8.0,
preferably
between 6.4 and 7.8. If required, the pH may be adjusted by using an acid,
such as
- hydrochloric acid, phosphoric acid or citric acid: or a basic compound such
as sodium
hydroxide, sodium dihydrogen phosphate dehydrate, sodium hydrogen phosphate,
sodium
hydrogen carbonate and sodium carbonate.
[000121] In another embodiment, the method may include the step of using a
solvent,
such as water. If water is used as a solvent, it is preferable to be removed
by freeze drying.
Kits
[000122] The present invention also provides a kit comprising a solid dosage
form of the
invention and Instructions for its use.
[000123] In a further aspect of the present invention, there is provided a kit
comprising:
a) the solid dosage form, wherein the dosage form comprises:
(i).at least one biologically active material, and
(ii) at least one matrix forming agent, and
b) instructions for Its use
, wherein
the dosage form substantially dissolves in the oral cavity. Preferably, the
solid
dosage form is a fast dissolving solid dosage form.
Preferably, the biologically active material is chosen from the list
comprising: at least one
cyclic guanosine monophosphate (cOMP) phosphodiesterase type 5 (PDE5)
Inhibitor, an
active material that binds to one or more adrenergic receptors, and an W-
methyl-D-aspartate
receptor antagonist. Preferably, the N-methyl-D-aspartate receptor antagonist
is chosen
from the list comprising: dextromethorphan, dextrorphan or ketamine.
Preferably, the active
material that binds to one or more adrenergic receptors is adrenaline, or an
adrenaline salt.
Preferably, the cyclic guanosine monophosphate (cGMP) phosphodiesterase type 5
(PDE5)
Inhibitor Is slIdenafil or a pharmaceutically acceptable salt thereof.
Preferably, the sildenafil
salt is sildenafil citrate.
Method of Treatment
[000124] Therapeutic uses of the solid dosage forms of the invention include
pain relief,
anti-inflammatory activity, migraine treatment, asthma treatment, and
treatment of other

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disorders that require the biologically active material to be administered
with a high
bioavailability and rapid activity.
[000125] The present Invention therefore provides a method of treating a
disease or
disorder in a patient comprising the step of: administering to the patient a
pharmaceutical
composition comprising the solid dosage form of the invention. Preferably, the
solid dosage
form is a fast dissolving solid dosage form.
[000126] One of the main areas when rapid bioavailability of a biologically
active material
Is rewired is in the relief of paln. The minor analgesics, such as cyclo-
oxygenase inhibitors
(aspirin related drugs) or opiolds may be prepared as medicaments according to
the present
invention. Alternatively, N-methyl-D-aspartate receptor antagonists may be
used for pain
relief and anaesthetics. Preferably, the N-methyl-D-aspartate receptor
antagonist is chosen
from the list comprising: dextromethorphan, dextrorphan or ketamine. The N-
methyl-D-
aspartate receptor antagonist may also be administered for the purpose of
depression
treatment, addiction treatment.
[000127] The invention therefore provides a method for providing pain relief,
comprising
the step of: administering to the patient a pharmaceutical composition
comprising the solid
dosage form of the invention comprising an N-methyl-D-aspartate receptor
antagonist.
[000128] The invention also provides a method for providing anaesthesia,
comprising the
step of; administering to the patient a pharmaceutical composition comprising
the solid
dosage form of the invention comprising an N-methyl-D-aspartate receptor
antagonist.
Preferably, the N-methyl-D-aspartate receptor antagonist is chosen from the
list comprising:
dextromethorphan, dextrorphan or ketamine.
[000129] The invention also provides a method of treating depression,
comprising the step
of: administering to the patient a pharmaceutical composition comprising the
solid dosage
form of the invention comprising an N-methyl-D-aspartate receptor antagonist.
Preferably,
the N-methyl-D-aspartate receptor antagonist is chosen from the list
comprising:
dextromethorphan, dextrorphan or ketamine.
[000130] The invention also provides a method of treating addiction,
comprising the step
of: administering to the patient a pharmaceutical composition comprising the
solid dosage
form of the Invention comprising an N-methyl-D-aspartate receptor antagonist.
Preferably,
the N-methyl-D-aspartate receptor antagonist is chosen from the list
comprising:
dextromethorphan, dextrorphan or ketamine.

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[000131] The N-methyl-D-aspartate receptor antagonist may also be administered
for the
purpose of treating an epileptic seizure. In one embodiment the epileptic
seizure is caused
by epilepsy. In a further embodiment, the epilepsy is selected from the group
consisting of:
benign Roiandic epilepsy, frontal lobe epilepsy, infantile spasms, juvenile
myoclonic
epilepsy, juvenile absence epilepsy, childhood absence epilepsy (pyknoiepsy),
hot water
epilepsy, Lennox-Gastaut syndrome, Landau-Kleffner syndrome, Dravet syndrome,
progressive myoclonus epilepsies, reflex epilepsy, Rasmussen's syndrome,
temporal lobe -
epilepsy, limbic epilepsy, status epilepticus, abdominal epilepsy, massive
bilateral
myoclonus, catamenial epilepsy, Jacksonian seizure disorder, Lafora disease,
and
photosensitive epilepsy. In a further embodiment, the epileptic seizure is
selected from the
group consisting of: nonconvulsiveStatus epilepticus and convulsive status
epilepticus.
[000132] The invention therefore provides a method of treating an epileptic
seizure,
comprising the step of administering to the patient a pharmaceutical
composition comprising
the solid dosage form of the invention comprising an N-methyl-D-aspartate
receptor
antagonist. Preferably, the N-methyl-D-aspartate receptor antagonist is chosen
from the list
comprising: dextromethorphan, dextrorphan or ketamine.
[000133] Treatment of cardiovascular disease may also benefit from
biologically active
materials in a solid dosage form according to the invention, such as treatment
of angina
pectoris and, In particular, molsidomine may benefit from improved
bioavailability. In another
example, adrenaline may be administered as a solid dosage form for therapy of
acute
cardiovascular events such as cardiac arrest or cardiac dysrhythmia.
Alternatively, other
active materials that bind to one or more adrenergic receptors, such as
noradrenaline, may
be used in the solid dosage form for the treatment of cardiovascular events.
[000134) Other therapeutic uses for biologically active materials in a solid
dosage form
according to the present Invention Include treatment of hair loss, sexual
dysfunction, or
psoriasis. If the solid dosage form of the present invention is being used to
treat sexual
dysfunction, the dosage form would preferably contain a cydlic guanosine
monophosphate
(cGMP) phosphodiesterase type 5 (PDE5) inhibitor. Preferably, the cyclic
guanosfne
monophosphate (cGMP) phosphodiesterase type 5 (PDE5) inhibitor is sildenafil
or a
pharmaceutically acceptable salt thereof. Preferably, the sildenafil salt is
sildenafil citrate.
[000135] The invention therefore provides a method for treating sexual
dysfunction,
comprising the step of: administering to the patient a pharmaceutical
composition comprising
the solid dosage form of the invention comprising at least one cyclic
guanosine
monophosphate (cGMP) phosphodiesterase type 6 (PDE5) Inhibitor. Preferably,
the cyclic
guanosine monophosphate (cGMP) phosphodiesterase type 5 (PDE5) inhibitor is
sildenafil

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or a pharmaceutically acceptable salt thereof. Preferably, the sildenafil salt
is sildenafil
citrate.
[000136] An additional use for the solid dosage form of the present Invention
containing a
cyclic guanosine monophosphate (cGMP) phosphodiesterase type 5 (PDE5)
inhibitor is the
treatment of pulmonary hypertension. Preferably, the cyclic guanosine
monophosphate
(cGMP) phosphodiesterase type 5 (PDE5) inhibitor is sildenafil or a
pharmaceutically
acceptable salt thereof. Preferably, the sildenafil salt is sildenafil
citrate.
[000137] The invention therefore provides a method for treating pulmonary
hypertension,
comprising the step of: administering to the patient a pharmaceutical
composition comprising
the solid dosage form of the invention comprising at least one cyclic
guanosine
monophosphate (cGMP) phosphodiesterase type 5 (PDE5) inhibitor. Preferably,
the cyclic
guanosine monophosphate (cGMP) phosphodiesterase type 5 (PDE5) inhibitor is
sildenafil
or a pharmaceutically acceptable salt thereof. Preferably, the sildenafil salt
is sildenafil
citrate.
[000138] Further therapeutic uses for biologically active materials in a solid
dosage form
according to the invention include allergy relief and anaphylaxis treatment.
Such disorders
benefit from the rapid absorption of biologically active materials such as
adrenaline and
other active materials that bind to one or more adrenergic receptors. =
[000139] The invention therefore provides a method for treating anaphylaxis,
comprising
the step of: administering to the patient a pharmaceutical composition
comprising the solid
dosage form of the invention comprising an active material that binds to one
or more
adrenergic receptors. The invention further provides a method for treating an
allergic
reaction, comprising the step of: administering to the patient a
pharmaceutical composition
comprising the solid dosage form of the invention comprising an active
material that binds to
one or more adrenergic receptors. Preferably, the active material that binds
to one or more
adrenergic receptors is adrenaline, or an adrenaline salt.
[000140] Preferably, the methods of treating comprise administering to the
patient a solid
dosage form of the Invention, wherein the dosage form is administered
sublingually.
Preferably, the solid dosage form is a fast dissolving solid dosage form.
= Administration
[000141] The solid dosage form of the present invention is suitable for oral
administration
to a subject. As discussed above, the dosage form comprises at least one
biologically active
material. The biologically active material is therefore delivered to the
subject via the oral

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cavity mucosa and into the systemic blood system within a relatively short
period of time.
Preferably, the solid dosage form is a fast dissolving solid dosage form.
[000142] in a preferred embodiment, an effective plasma concentration of the
biologically
active material is reached within a period of no more than two hours,
preferable within 30
minutes, 20 minutes, 15 minutes or less than 15 minutes. Most preferably, the
effective
plasma concentration of the biologically active material is reached within a
period of 10
minutes, 9 minutes, 8 minutes, 7 minutes, 8 minutes, 5 minutes, 4 minutes, 3
minutes or 2
minutes. For example, a solid dosage form of the present invention in the form
of a
sublingual fentanyl wafer may result in detectable plasma fentanyl within 2 to
10 minutes,
occurring in most cases within 5 minutes after administration. In other
examples, an
adrenaline solid dosage form of the present invention may be therapeutic
within 5 minutes; a
sildenafil solid dosage form within 20 minutes and a ketamine fast dissolving
solid dosage
form may be therapeutic within 10 minutes.
[000143] In another embodiment, the dosage form provides the patient with a
peak
plasma concentration (Cõ,õx) of the biologically active material selected from
the group
consisting of: 25rig/m1; 30ng/m1; 40ng/m1; 5Ong/m1; 60ng/m1; long/m1; 80ng/m1;
90ng/m1;
100ng/m1; 11Ong/m1; 120ng/m1; 13Ong/m1; 140ng/m1; 15Ong/m1; 16Ong/m1;
17Ong/m1;
180ng/m1; 190ng/m1; and 200ng/ml.
[000144] When compare with intravenous injection, a solid dosage form of the
present
Invention in the form of a sublingual wafer may produce a much lower Cm, which
may
reduce the toxicity of the biologically active material being administered.
For example, in a
Phase I sublingual fentanyl wafer clinics( trial, the Cniaõ of a 100 pg
fentanyl Intravenous
infusion (5 min) was 1451.0 pg/mL, however the Cmõ of a 100 pg fentanyl wafer
was only
219.3 pg/mt... Similarly, in a Phase 1 sublingual ketamine wafer clinical
trial, the Cõ,õ4 of a 10
mg ketamine intravenous infusion (30 min) was 128_1 ng/m1., whereas the cm of
a 25 mg
ketamine wafer was 71.1 ng/mL.
[000145] In another embodiment, the solid' dosage form has a median t of
the
biologically active material selected from the group consisting of: between 5
minutes to 90
minutes; between 10 minutes and 75 Minutes; between 15 minutes and 60 minutes;
between 30 minutes and 50 minutes; between 40 minutes and 50 minutes; and 45
minutes.
For example, the Tn," for a 25 mg ketamine wafer form of the solid dosage form
of the
present invention may be 45 minutes.
[000146] In a highly preferred embodiment, the dosage form provides the first
detectable
plasma concentration of the biologically active material selected from the
group consisting

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of: within 15 minutes; within 14 minutes; within 13 minutes; within 12
minutes; within 11
minutes; within 10 minutes; within 9 minutes; within 8 minutes; within 7
minutes; within 6
minutes; within 5 minutes; within 4 minutes; within 3 minutes; within 2
minutes; and within 1
minute. For example, the first detectable plasma fentanyl concentration, after
sublingual
administration with a dosage form of the present invention, may be observed
between 2 and
minutes after administration.
[000147] Preferably, the dosage form provides a median bioavailability of the
biologically
active material in a patient, selected from the group consisting of: between
10 and 60%;
between 20 and 40%; between 25 and 35%; between 28 and 30%; and 28%. For
example,
the solid dosage form may provide a median bioavailability of an N-methyl-D-
aspartate
receptor antagonist in a patient of 28% wherein the dose of the antagonist is
25mg. The
solid dosage form may also provide, a median bioavailability of sublingual
ketamine of 29%
wherein the dose of ketamine is 25mg.
[000148] In another embodiment, the solid dosage form provides the patient
with an ,
effective therapeutic plasma level of the biologically active material over a
period selected
from the group consisting of: more than 30 minutes, 30 minutes, 25 to 30
minutes, 20 to 25
minutes, 15 to 20 minutes, 10 to 15 minutes, 10 minutes, 9 minutes, 8 minutes,
7 minutes, 6
minutes, 6 minutes, 4 minutes, 3 minutes, or two minutes.
[000149] The subject receiving the solid dosage form of the present invention
may be an
animal or human being. When the subject is a human being, It may be an adult
or a child,
Including elderly adults and infants. In particular the subject may be a
subject that Is unable
to or has difficulties in swallowing.
[000150] The present invention has surprisingly found that the addition of
sodium
carboxymethylcellulose improves the dissolution rate of the solid dosage form.
When the
amount of sodium carboxymethylcellulose is between about 0,1% and 15% by dry
weight of
the dosage form, the dosage form releases the active agent rapidly, without
leaving a
residue in the oral cavity. In addition, the use of gelatine is avoided, and
therefore little or no
unwanted residue was left in the oral cavity after administration. The
addition of lactose
and/or mannitol Is also advantageous in the solid dosage form of the present
invention.
Use
[000161] There is also provided the use of a solid dosage form adapted for the
release of
a biologically active material in the oral cavity wherein the dosage form
comprises:
(a) at least one biologically active material, and

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(b) at least one matrix forming agent, wherein the dosage form substantially
dissolves in
the oral cavity
in the manufacture of a medicament to treat a disease or disorder. Preferably,
the solid
dosage form is a fast dissolving solid dosage form.
[000152] Preferably, the biologically active material Is chosen from the list
comprising: at
least one cyclic guanosine monophosphate (cGMP) phosphodiesterase type 5
(PDE5)
inhibitor, an active material that binds to one or more adrenergic receptors,
and an N-methyl-
D-aspartate receptor antagonist Preferably, the N-methyl-D-aspartate receptor
antagonist
Is chosen from the list comprising: dextromethorphan, dextrorphan or ketamine.
Preferably,
the active material that binds to one or more adrenergic receptors is
adrenaline
(epinephrine), or an adrenaline salt. Preferably, the cyclic guanosine
monophosphate
(cGMP) phosphodiesterase type 5 (PDE5) inhibitor is sildenafil or a
pharmaceutically
acceptable salt thereof. Preferably, the sildenafil salt Is sildenafil
citrate.
[000153] Preferably the disease or disorder is selected from the list
comprising: pain,
depression, addiction, inflammation, migraine, asthma, epilepsy, acute
cardiovascular
events such as cardiac arrest or cardiac dysrhythmia, angina pectoris, hair
loss, sexual
dysfunction, psoriasis, pulmonary hypertension, allergy or anaphylaxis and the
provision of
anaesthesia.
[000154] There is therefore provided the use of a solid dosage form adapted
for the
release of a biologically active material in the oral cavity wherein the
dosage form comprises:
(a) at least one cyclic guanosine monophosphate (cOMP) phosphodiesterase type
5
(PDE5) inhibitor, and
(b) at least one matrix forming agent, wherein the dosage form substantially
dissolves in
the oral cavity
In the manufacture of a medicament to treat a disease or disorder. Preferably,
the solid
dosage form is a fast dissolving solid dosage form_ Preferably the disease or
disorder is
chosen from the list comprising: sexual dysfunction, pulmonary hypertension.
[000155] the use of a solid dosage form adapted for the release of a
biologically active
material in the oral cavity wherein the dosage form comprises:
(a) an N-methyl-D-aspartate receptor antagonist, and
(b) at least one matrix forming agent, wherein the dosage form substantially
dissolves in
the oral cavity

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in the manufacture of a medicament to treat a disease or disorder. Preferably,
the solid
dosage form is a fast dissolving solid dosage form. Preferably the disease or
disorder is
chosen from the list comprising: pain, depression, addiction, migraine,
epilepsy, and the
provision of anaesthesia.
1000158] the use of a solid dosage form adapted for the release of a
biologically active
material in the oral cavity wherein the dosage form comprises:
(a) an active material that binds to one or more adrenergic receptors, and
(b) at least one matrix forming agent, wherein the dosage form substantially
dissolves in
the oral cavity
in the manufacture of a medicament to treat a disease or disorder. Preferably,
the solid
dosage form is a fast dissolving solid dosage form. Preferably the disease or
disorder is
chosen from the list comprising: acute cardiovascular events such as cardiac
arrest or
cardiac dysrhythmia, angina pectoris, allergy or anaphylaxis.
General
[000157] Those skilled in the art will appreciate that the invention described
herein is
susceptible to variations and modifications other than those specifically
described. It is to be
understood that the invention includes all such variations and modifications.
The invention
also includes all of the steps, features, compositions and materials referred
to or indicated in
the specification, individually or collectively and any and all combinations
or any two or more
of the steps or features.
[000158] The= present invention is not to be limited in scope by the specific
embodiments
described herein, which are intended for the purpose of exemplification only.
Functionally
equivalent products, compositions and methods are clearly within the scope of
the invention
as described herein.
(000159] The invention described herein may include one or more ranges of
values (e.g.
size, concentration etc.). A range of values will be understood to Include all
values within the
range, including the values defining the range, and values adjacent to the
range that lead to
the same or substantially the same outcome as the values immediately adjacent
to that
value which defines the boundary to the range.
[000160] The entire disclosures of all publications (including patents, patent
applications,
journal articles, laboratory manuals, books, or other documents) cited herein
are hereby
incorporated by reference. Inclusion does not constitute an admission is made
that any of

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the references constitute prior art or are part of the common general
knowledge of those
working in the field to which this Invention relates.
[000161] Throughout this specification, unless the context requires otherwise,
the word.
"comprise" or variations, such as "comprises" or "comprising" will be
understood to imply the
inclusion of a stated integer, or group of integers, however not the exclusion
of any other
integers or group of integers. It is also noted that In this disclosure, and
particularly in the
claims and/or paragraphs, terms such as "comprises", "comprised", "comprising"
and the like
can have the meaning attributed to it in US Patent law: e.g., they can mean
"includes%
"included", Including", and the like.
[000162] "Therapeutically effective amount" as used herein with respect to
methods of
treatment and in particular drug dosage, shall mean that dosage that provides
the specific
pharmacological response for which the drug is administered in a significant
number of
subjects in need of such treatment. It is emphasized that "therapeutically
effective amount,"
administered to a particular subject in a particular instance will not always
be effective in
treating the diseases described herein, even though such dosage Is deemed a
"therapeutically effective amount" by those skilled in the art. It is to be
further understood
that drug dosages are, in particular instances, measured as oral dosages, or
with reference
to drug levels as measured in blood.
[000163] The term "inhibit" is defined to include its generally accepted
meaning which
Includes prohibiting, preventing, restraining, and lowering, stopping, or
reversing progression
or severity, and such action on a resultant symptom. As such the present
invention includes
both medical therapeutic and prophylactic administration, as appropriate.
[000164] The term "biologically active material" is defined to mean a
biologically active
compound or a substance which comprises a biologically active compound. In
this definition,
a compound is generally taken to mean a distinct chemical entity where a
chemical formula
or formulas can be used to describe the substance. Such compounds would
generally,
however not necessarily be identified in the literature by a unique
classification system such
as a CAS number. Some compounds may have a more complex and have a mixed
chemical
structure. For such compounds they may only have an empirical formula or be
qualitatively
Identified. A compound would generally be a pure material, although it would
be expected
that up to 10%, 20%, 30%, 40%, 50%, 60%, 70%, 80%, 90% of the substance could
be
other, impurities and the like. Examples of biologically active compounds are,
however not
limited to, fungicides, pesticides, herbicides, seed treatments,
cosmeceuticals, cosmetics,
complementary medicines, natural ,products, vitamins, nutrients,
neutraceuticals,
pharmaceutical actives, biologics, amino acids, proteins, peptides,
nucleotides, nucleic

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acids, additives, foods and food Ingredients and analogues, homotogs and first
order
derivatives thereof. A substance that contains a biological active compound is
any substance
which has as one of its components a biological active compound. Examples of
substances
containing biologically active compounds are, however not limited to,
pharmaceutical
formulations and products, cosmetic formulations and products, Industrial
formulations and
products, agricultural formulations and products, foods, seeds, cocoa and
cocoa solids,
coffee, herbs, spices, other plant materials, minerals, animal products,
shells and other
skeletal material.
[0001651 Any of the terms, "biological(ly) active", "active", "active
material" shall have the
same meaning as biologically active material.
[000166] As used herein "pharmaceutically acceptable carrier" includes any and
all
solvents, dispersion media, coatings, antibacterial and antifungal agents,
isotonic and
absorption delaying agents, and the like that are physiologically compatible.
Preferably, the
carrier Is suitable for oral administration.
BRIEF DESCRIPTION OF THE DRAWINGS
FIGURE 1 Scanning
electron micrographs of the surface of wafers from batch
numbers 0715018 and 0715028.
FIGURE 2 Scanning
electron micrographs of the surface of wafers from batch
numbers 0820A and 0820B.
FIGURE 3 Scanning
electron micrograph of the surface of wafer from batch ,
number 0905MD.
FIGURE 4 Scanning
electron micrographs of the cross section of wafers from
batch numbers 0715018 and 071502B.
FIGURE 5 Scanning
electron micrographs of the cross section of wafers from
batch numbers 0820A and 08208.
FIGURE 6 Scanning
electron micrograph of the cross sectiOn of wafer from batch
number 0905MD.
FIGURE 7 Powder X-ray
diffraction spectra of wafers from batch number 071501A
and 0715028.

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FIGURE 8 Powder X-ray diffraction spectra of Wafers from batch numbers
0820A
and 0820B.
FIGURE 9 Powder X-ray diffraction spectrum of wafer from batch number
0905MD.
FIGURE 10 [A) Typical HPLC chromatograms of standard midazolam sample at
4.05 pg/mL (n=3); [B] Midazolam powder dissolution samples at 1
minute and 5 minutes; [C] Midazolam powder dissolution sample at 10
minutes; 11)) Midazolam powder dissolution sample 15 minutes; and 1E]
standard midazolam sample at 8.1 pg/ml.
FIGURE 11 Typical HPLC chromatograms of dissolution wafer Sample 81 at 45
seconds and 1 minute.
FIGURE 12 Typical HPLC chromatogram of dissolution wafer Sample S1 at 10
minutes.
FIGURE 13 Typical HPLC chromatograms of dissolution wafer Sample S2 at 5
and
minutes.
FIGURE 14 Typical HPLC chromatograms of dissolution wafer Sample S2 at 30
seconds and 2 minutes.
FIGURE 16 Typical HPLC chromatograms of dissolution wafer Sample 63 at 20
seconds and at 1 minute,
FIGURE 16 Typical HPLC chromatograms of standard midazolam sample at 1.01
pg/mL.
FIGURE 17 Typical HPLC chromatograms of Midazolam powder dissolution
sample
at 30 seconds.
FIGURE 18 Typical HPLC chromatograms of dissolution wafer 1 at 1 minute
and 5
minutes.
FIGURE 19 Typical HPLC chromatograms of dissolution wafer 1 at 6, 10 and
15
minutes.
FIGURE 20 Typical HPLC chromatogram of drug loading test wafer sample
No.1.
FIGURE 21 Typical HPLC chromatograms of dissolution wafer 2 at 30 seconds.
FIGURE 22 Typical HPLC chromatograms of dissolution wafer 2 at 1 minute
and 5
minutes.

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FIGURE 23 Typical HPLC chromatograms of dissolution wafer 2 at 10, 15 and
30
minutes.
FIGURE 24 Typical HPLC chromatograms of drug loading test wafer sample No.
2_
FIGURE 26 Typical HPLC chromatograms of dissolution wafer 3 at 30 seconds.
FIGURE 26 Typical HPLC chromatograms of dissolution wafer 3 at 1 minute
and 5
minutes.
FIGURE 27 Typical HPLC chromatograms of dissolution wafer 3 at 10 and 15
minutes.
FIGURE 28 Typical HPLC chromatograms of dissolution wafer 3 at 30, 45 and
60
minutes.
FIGURE 29 Typical HPLC chromatograms of drug loading test wafer sample No.
3.
FIGURE 30 Standard HPLC calibration curve of midazolam (1 to 32,4 pg/mL).
FIGURE 31 Cumulative concentration of midazolam released from wafer and
midazolam powder in phosphate buffer solution (pH 6.8) at 37 C.
FIGURE 32 Standard HPLC calibration curve of fentanyl (0.5 to 10 p.g/mL).
FIGURE 33 Dissolution profiles of fentanyl wafer in phosphate buffer
solution (pH
6.8) at 37 C, (n=4).
FIGURE 34 A to E Typical HPLC chromatograms of dissolution samples 1 to 3 of
fentanyl
wafers at sampling times of 0.5, 1, 5, 10, 15 and 20 minutes,
FIGURE 35 A to J Typical HPLC chromatograms of dissolution samples 4 to 6 of
fentanyl
wafers at sampling times of 1,2, 3,4, 5, 7 and 10 minutes.
FIGURE 36 Scanning electron micrographs of the surface of a blank fast
dissolving
dosage form.
FIGURE 37 Scanning electron micrographs of the surface of ketamine fast
dissolving dosage form.
FIGURE 38 Powder X-ray diffraction spectra of a blank fast dissolving
dosage form.
FIGURE 39 Powder X-ray diffraction spectra of ketamine powder.
FIGURE 40 Powder X-ray diffraction spectrum of ketamine fast dissolving
dosage
form.

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FIGURE 41 Typical HPLC chromatograms of dissolution ketamine wafer
Sample 62
at 1 minute.
FIGURE 42 Typical HPLC
chromatogram of dissolution ketamine wafer Sample S2
at 3 minutes.
FIGURE 43 Typical HPLC
chromatograms of dissolution ketamine wafer Sample 52
at 5 minutes.
FIGURE 44 Typical HPLC
chromatograms of dissolution ketamine wafer Sample S2
at 7 minutes.
FIGURE 46 Typical HPLC
chromatograms of dissolution ketamine wafer Sample 62
at 10 minutes.
FIGURE 46 Typical HPLC
chromatograms of dissolution ketamine wafer Sample 62
at 15 minutes.
FIGURE 47 Typical HPLC
chromatograms of dissolution ketamine wafer Sample $2
at 20 minutes.
FIGURE 48 Typical HPLC
chromatograms of dissolution ketamine wafer Samples
S2 at 30 minutes.
FIGURE 49 Standard
HPLC calibration curve of ketamine hydrochloride (5 to
100 g/mL).
FIGURE 60 Typical HPLC
chromatogram of drug loading test ketamine wafter
sample No. 1.
FIGURE 61 Dissolution
profiles of ketamine wafer in phosphate buffer solution (pH
6.8) at 37 C, (n=3).
FIGURE 62 Geometric
mean with overlay of Individual RS ketamine plasma
concentrations for the entire sampling period, following a 10 mg dose
given during a 30 minute intravenous infusion to eight healthy
volunteers.
FIGURE 63 Geometric
mean with overlay of individual RS ketamine plasma
concentrations during the first 12 hours following a '10 mg dose given
during a 30 minute intravenous infusion to eight healthy volunteers.

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= FIGURE 54 Geometric mean With an overlay of individual
RS ketamine plasma
concentrations for the entire sampling period, following a 25 mg
= sublingual dose to eight healthy volunteers.
FIGURE 66 Geometric mean with overlay of individual RS ketamine
plasma
concentrations during the first 12 hours following a 25 mg sublingual
dose to eight healthy volunteers.
FIGURE 66 Individual (S=Subject randomization number) tf,,,,õ for
RS ketamine
= following 25 mg sublingual dose to eight healthy volunteers.
FIGURE 67 individual (St--Subject randomization number) AUCINF for
RS ketamine
following a 10 mg dose given during a 30 minute intravenous infusion
(IV, open bars) or 25 mg sublingually (St., filled bars) to eight healthy
volunteers.
FIGURE 68 Individual (Subject randomization number) clearance (CL)
for RS
ketamine following a 10 mg dose given during a 30 minute Intravenous
infusion to eight healthy volunteers.
FIGURE 69 individual (S=Subject randomization number) terminal half-
life timfor RS
ketamine following a 10 mg dose given during a 30 minutes intravenous
infusion (IV, open circles) or 25 mg sublingually (SL, filled circles) to
eight healthy volunteers.
FIGURE 60 Individual estimates for all subjects (Sr -*subject
number) of bioavailability
(F) % following administration of 25 mg RS ketamine to eight healthy
Volunteers.
FIGURE 61 Mood rating scale profile for IV administration. The mean
(SD) scores
for Factors "alertness" (Factor 1), "contentedness" (Factor 2) and
"calmness" (Factor 3) observed following a 30 minute intravenous
infusion of 10 mg ketamine to healthy volunteers.
FIGURE 62 Mood rating scale profile for sublingual administration_
The mean (SD)
scores for Factors "alertness" (Factor 1), "contentedness" (Factor 2) and
"calmness" (Factor 3) observed following sublingual administration of a
25 mg ketamine wafer to healthy volunteers.
= FIGURE 63 Total modified Likert Scales of local
tolerability

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FIGURE 64 Scanning electron micrographs of the surface of a blank
fast dissolving
dosage form.
FIGURE 66 Powder X-ray diffraction spectra of a blank fast
dissolving dosage form. ,
= FIGURE 66 Powder X-ray diffraction spectra of
sildenafil powder.
FIGURE 67 Powder X-ray diffraction spectrum of sildenafil fast
dissolving dosage
form.
FIGURE 68 Typical HPLC chromatograms of dissolution sildenafil
wafer Sample S1
at 1 minute.
FIGURE 69 Typical HPLC chromatogram of dissolution sildenafil wafer
Sample S1
at 3 minutes.
FIGURE 70 Typical HPLC chromatograms of dissolution sildenafil
wafer Sample S1
at 5 minutes.
FIGURE 71 Typical HPLC chromatograms of dissolution sildenafil
wafer Sample Si
at 7 minutes.
FIGURE 72 Typical HPLC chromatograms of dissolution sildenafil
wafer Sample S1
at 10 minutes.
FIGURE 73 Typical HPLC chromatograms of dissolution sildenafil
wafer Sample Si
at 15 minutes.
FIGURE 74 Typical HPLC chromatograms of dissolution sildenafil
wafer Sample S1
at 20 minutes.
FIGURE 76 Typical HPLC chromatograms of dissolution sildenafil
wafer Sample S1
at 30 minutes_
FIGURE 76 Typical FIPLC chromatogram of drug loading test sildenafil
wafter
sample No.1.
FIGURE 77 Standard HPLC calibration curve of sildenafil 5 to 100
gtmL).
FIGURE 78 Dissolution profiles of sildenafil wafer in phosphate
buffer solution (pH
6.8) at 37 C, (n=4).
FIGURE 79 Table showing the demographic characteristics of the study
volunteers
according to example 4.

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FIGURE BO Graph showing the mean ( SEM) plasma concentration (pg/mL) over
time profiles for sublingual fentanyl water and IV fentanyl. Inset figure is
an expanded profile for the initial two-hour period.
FIGURE 81 Graph showing the plasma concentration data (pg/mL) over time
profiles for sublingual fentanyl wafer for each volunteer (nr-22).
FIGURE 82 Table showing the mean values ( 1 SD) of fentanyl plasma
pharmacokinetic parameters.
FIGURE 83 Table showing the comparative literature pharmacokinetic data
(mean
1 SD) for buccal and sublingual (SL) fentanyl dosage forms.

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EXAMPLES
[000167] The present invention will now be described with reference to the
following non-
limiting Examples. The description of the Examples is in no way limiting on
the preceding
paragraphs of this specification, however is provided for exemplification of
the methods and
compositions of the Invention.
EXample 1
[000168] A formulation of the present invention, in the form of a solid dosage
form (wafer),
was prepared In accordance with the method and ingredients as set out below in
Table 1:
Table 1: Fast Dissolving Solid Dosage Form (Wafer) Formulation
Ingredient Amount (g) % by weight
Sodium carbonate BP/USP 10 0.075
Sodium 20 0.149
carboxymethylcellulose
BP/USP
Polyethylene glycol 2000 50 0.374
BPJUSP
Glycine BP/USP 100 0.747
Microcrystalline cellulose 200 1.495
BP/USP
AmylopectIn BP/USP 500 3.737
Lactose BP/USP 1000 7.474
Mannitol BP/USP 1500 11.211
Purified water BP/USP 10000 74.738
[000168] Sodium carboxymethylcellulose and amylopectin were added in a portion
of
purified water by mixing thoroughly with a stirrer. The mixture was then
heated to 50 C for
ten minutes to allow dissolving of the polymers. Once the solution cooled down
to room
temperature, polyethylene glycol 2000, glycine, sodium carbonate,
microcrystalline cellulose,
lactose and mannitol were added individually, under stirring to obtain a
homogenousiy
solution. The viscosity of the solution was measured at 25 C using a
Brookfield Digital
Viscometer (Brookfield Engineering Laboratories Inc., MA, USA).
[000170] The resulting mixture was transferred by pipette arid accurately
weighed into pre-
formed blister packs, and then transferred into a freezer (-30 C) for
approximately 24 hours.
After freezing, the sample was freeze-dried (DYNAVAC, Australia) for 24 hours.
The
prepare sample was stored in desiccator over silica gel at a room temperature.

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1000171) The following additional wafer formulations were prepared by the
method as set
out above. Essentially Samples 1 to 6 are based on the formulation described
above, with
the addition of flavour and/or colour agents.
Sample 1. Additionally contained a flavour.
Ingredient Amount (9) = % by weight
= Sodium carbonate 1 . 0.08
Sodium 2 0.15
carboxymethylcellulose
Polyethylene glycol 2000 5 0.37
Orange flavour 10 0.74
Glyclne 10 0.74
Microcrystalline cellulose 20 1,48
AMylopectin 50 s 3.71
Lactose 100 7.42
Mannitoi 150 11,13
Purified water 1000 74.18
=
Sample 2. Additionally contained a flavour and a pH adjuster (citric acid).
Ingredient Amount (g) % by weight
Sodium carbonate 1 0,07
= Sodium 2 0715
carboxymethylcellulose
Citric acid 6 0.37
Polyethylene glycol 2000 5 0:37
Mint flavour 10 0.74
Glycine 10 0.74
Microcrystalline cellulose 20 1.48
Amylopectin 50 = 3.70
Lactose 100 7.39
Mannitol 150 11.09
Purified water 1000 73.91

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Sample 3. Additionally contained flavour and a colouring agent
Ingredient Amount (g) % by weight
FO & C red 0.1 0.01
Sodium carbonate 1 0.07
Sodium 2 0.16
carboxymethylcellulose
Polyethylene glycol 2000 6 0.37
Grape flavour 9.9 0.74
Glycine 10 0,74
¨ Micr - ocrystalline cellulose 20 1.48
Amylopectin 60 3.71
Lactose 100 7A2
Mannitol 150 11.13
Purified water 1000 ¨ 74.18
Sample 4. Additionally contained flavour, a colouring agent and an absorption
enhancer.
Ingredient Amount (g) % by weight
FD .& C blue 0.1 0.01
Sodium carbonate 1 0.07
,Sodium 2 0.15
oarboxymethylcellulose
p-Cyolodextrin 5 0.3'7
Polyethylene glycol 2000 6 0.37
Grape flavour. 9.9 0.73
Glyclne 10 0.74
Microcrystalline cellulose 20 1.48
Amylopectin 60 3.71
Lactose 100 7,42
Mannitol 145 10.76
Purified water 1000 74.19
=

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=
51
Sample 5. Additionally contained a colouring agent and a sweetener
Ingredient Amount (g) % by weight
Ft) & C red - = 0.1 0.01
Sodium carbonate 1 0.07
Sodium 2 0.15
carboxymethylcellulose
Aspartame 5 0.37
Polyethylene glycol 2000 5 (137
Cherry flavour 9.9 0.73 "
Glycine 10
0.74
Microorystalline cellulose 20 1.48
Amylopectin 50 3.71
Lactose 100 7.42
Mannitol 145 10.76
Purified water 1000 74.19
=
Sample 6. Additionally contained a colouring agent and a pH adjuster
Ingredient Amount (g) % by weight
ro & C red 0.1 0.01
Sodium carbonate 1 0.07
Sodium 2 0.15
carboxymethylceltulose
Sodium hydrogen 6 0.37
carbonate
Polyethylene glycol 2000 5 0.37
Raspberry flavour 9.9 0.73
Glycine 10 0.74
Microcrystalline cellulose 20 1.48
=
Amylopectin 50 1 3.71
Lactose 100 7.42
MannItol 146 10.76
_
Purified water 1000 74.19
[000172] Various batches of the solid dosage wafer form were then prepared
based on the
formulation shown in Table 1 and prepared as set out above, also containing
midazotam
(base) or fentanyt citrate (2.6 mg fentanyl base for 50 wafers, Strength
equivalent of 50 pg
fentanyl base) as the biologically active material. The batch number and the
ingredients are
listed in Table 2.

,
52
Table 2: Midazolam or Fentanyl Compositions Used for Investigations
Batch Batch Batch Batch Batch Batch
071501B 0715028 0620A 08208 0906MD 1003FEN
. Ingredient Amount Amount Amount _ Amount
Amount Amount
(9) (9) (g) WI 40 40
_ _
Arnylopectin = 1.0 ' 1.0 1.0 0.00 1.0 ' 0.5
_ .
Mannitol ' 3= .0 3.0 ' 3.0 3.0 3.0 1.5
lactose , 2.0 2.0 2.0 2.0 2.0 ' 1.0
Glycine 0.2 a- 02 0_5 03 0.2 0.1
_
-PEG 2000 ' 0= .1 0.1 0.1 - 0.1 0.1 0.05
- - -
Sodium 0.04 0.04 0.04 a 0.04 0.04 0.02
Carboxymethyl-
- cellulose
_ =
-Sodium carbonate 0 0.02 0 0 0.02 ' 0.01
_
Starch 1.0 0 -0 ' 0 0 0
_ -Avicel TM - 0= .2 a' 0.2' 0.00 0.2 - 0.2
0.1
_ -Active 0 o -0 .-0 0.255 . 0.004
pharmaceutical midazolarn fontanyl
Ingredient (base) citrate (2.6
= mg
' fentanyt
base)
Purified water 40 40 40 40 40 20
General observations
(000173/ It was found that there was no significant difference between the use
of
polyethylene glycol 1000 or polyethylene glycol 2000 in the wafer formulation
(results not
shown). = .
(0001741 The addition of starch resulted in a hard wafer, and was less
suitable for the fast
dissolving solid dosage form of the present invention.
Uniformity of Weight
(000175) The uniformity of the weight of the fast dissolving dosage wafer form
was tested
in accordance with the British Pharmacopoeia (BP) 2009 test. Twenty wafers
from each of
the formulations listed in Table 2 were individually weighed, and the average
weight and
=
=
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relative standard was calculated. All the prepared wafers from different
formulations were
within the accepted weight variation from between 0.26 to 2%.
Hardness
[000176] The hardness of the dosage formulations listed in Table 2 Was also
tested. The
mechanical strength of a tablet is referred to as "hardness". The hardness of
the wafer was
determined using an Erweka Hardness Tester (Germany). The values of hardness
from
different formulations ranged from 0.5 to 4.0 kg_ It was observed that the
hardness of the
formulation increased when Avicel was added to the formulation (results not
shown).
Friability
[000177] The strength of the fast dissolving solid dosage wafer forms, i.e.
their ability to be
reduced from a solid substance into smaller pieces was measured. The test was
conducted
according to BP 2009 method (i.e. friability of uncoated tablets), using the
Etweka friability
tester (Germany). A sample of 20 wafers was weighed accurately and placed in
the
apparatus. A rotation time of four minutes at 25 rpm was used. Wafers were
removed and
reweighed and the percentage weight loss was calculated. It was found that the
weight loss
of the 20 wafers ranged from 8 to 20%. Although this weight loss does not
comply with the
BP 2009 standard of about 1% weight loss for compressed tablets, there Is no
such standard
for wafers in either the BP or USP monograph.
Moisture Analysis
[000178] The moisture content of the wafers was analysed after lyophilisation
using the
870 Karl Fisher Titrino Plus (Metrohm Ag, Germany). The results show that the
residual
moisture content varied between 1% to 5% for different formulations.
Scanning electron microscopic analysis
[000179] Surface morphology and cross-sections of selected wafer formulations
were
observed using scanning electron microscope (SEM) (Zeiss, EVO 40 XVP, the
Oxford
Instrument, UK). Cross-section sample were prepared by cutting a thin slice of
the wafer
using a scalpel. Samples were coated with carbon prior to examination. The
accelerating
voltage was 10 kV.
[000180] The SEM images shown In Figures 1 to 6 illustrate the highly porous
nature of
the wafers on both surface and the inner structure. Clearly, there were
morphological
differences between different formulations. These differences indicated that
the excipients
used influence the microstructure of the wafer. In addition, the
microstructure might give an

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explanation about the different hardness, friability, disintegration time, and
even the
dissolution profiles of wafer prepared from different formulations.
Powder X-ray diffraction (XRD)
[000181] X-ray diffraction experiments were performed using Bruker 08 Advance
, (Germany) with detector LynEye. The radiation used was nickel filtered CuKa,
which was
generated using an acceleration voltage of 40 kV and a cathode current of 40
mA. The
samples were scanned over a 2 theta range of 7.5 to 70 degree, and counting
time at 1
second per 0.02 degree.
[000182] The physical state of the materials in the wafer was evident in the X-
ray
diffraction spectra. Spectra for three different formulations as prepared in
accordance with
Table 2 are shown in Figures 7 to 9. It was observed that all the powder
patterns of wafer
prepared are dominated by intense scattering peaks approximately located at 2-
theta of
9,58 , 19, 68 and 20.05 , which indicating a crystalline nature, This finding
was also
supported by the data generated from the SEM (see Figures 1-6). Indeed, the
excipients
used in the formulations, such as glycine, lactose, mannitol and
microcrystalline cellulose
are crystalline In nature. It was observed that there was minimal physical
state change In
the solid dispersion.
Disintegration and Dissolution Analysis
[000183] Disintegration and dissolution tests were carried out using Apparatus
I (BP 2009,
Basket apparatus). The Erweka dissolution apparatus (Hesenstamm, Germany) was
used
for both tests. The temperature of the medium was kept at 37 0.5 C.
[0001841 For the disintegration test, a wafer was placed in the cylindrical
basket and
wetted on the underside by contact with distilled water in the cylindrical
vessel. The time of
total dissolution of each wafer was noted, and a mean value was calculated,
[000185] For the dissolution testing a wafer (Batch 0905MD) containing
midazoiam as a
model drug was used to determine the mechanism of drug release from the system
following
the both BP basket and USP paddle methods (see Figure 17). Dissolution medium
was 500
rnt_ phosphate buffer solution (pH value is closed to saliva fluid at 6.8),
with a paddle rotation
speed at 75 rpm_ At given interval (e_g_, 0_5, 1, 2, 3, 5 10 15, 20 and 30
min), 2 mL of
solution was sampled and replaced with an equal volume of fresh medium to
maintain a
constant total volume. Samples were filtered through a 0.2 pm Millipore
filter. The drug
released was measured by HPLC.

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1000186] The HPLC system consisted of a Waters 1525 pump, a Waters Symmetry
C18
column (5 am, 150 X 4.6 mm), and Waters UV 484 detector_ The mobile phase was
acetonitrile: 10 mM ammonium acetate buffer (40 : 60, v/v, pH 4.10) and the
flow rate was
1.2 mf/min at ambient temperature. The peaks were recorded at 220 nm, and the
limit of =
quantitation was approximately 1 ng/ml. The calibration curve for the
concentrations 1-32.4
lig/mL (six-point calibration) was linear br=870714x+52057 (r=0.9998), y
representing the
peak area of midazolam and x the concentration of the samples].
[0001871 A standard HPLC calibration curve for midazolam is shown in Figure
30. The
results as shown in Figure 31 demonstrate that the average disintegration
times were less
than 15 seconds; and the dissolution studies also indicated a fast release
rate of midazolam,
Almost 75% of midazolam had dissolved in one minute. The raw midazolam powder
was
considerably slower. This may indicate the changing of midazolam crystal form
in the wafer,
which was also evident in the X-ray. The X-ray spectrum pointed to an
amorphization of
midazolam during the freeze-drying process.
[000188] The results of the HPLC analysis on various samples of the
formulation as
prepared in accordance with Table 1 are shown in Figures 11 to 29. Figures 10
A to 10 E
illustrate the HPLC of standard midazolam sample, and midazolam powder
dissolution
samples. Figures 11 to 16 are HPLC chromatograms of dissolution wafer samples
1 to 3
(S1, S2 and S3. BP basket method). .13riefly, the samples 1, 2 and 3 were
prepared
according to Table 1 and are triplicate samples of the same formulation.
Figure 17 illustrates
the HPLC chromatogram of Batch 0905MD, which contains midazolam as a model
drug.
[000189) Figures 18 to 29 reflect the HPLC chromatograms of another three
dissolution
wafer samples (USP paddle methods), As discussed above, the dissolution rate
of the wafer
containing test drug midazolam was measured. Samples were taken at 0.5 minute,
1
minute, 5, minutes, 10 minutes and 15 minutes.
[000190] The results of wafers 1 to 3 (Batch 0905M0) are shown over these time
limits in
Figures 18 to 29. A drug loading test was also conducted for another three
wafers (Batch
0905MD).
[000191] it was shown that the wafers of the present Invention were able to
cornpletely
dissolve in about 15 seconds and did not leave behind any residue,
[000192] A wafer (Batch 1003 FEN) containing fentanyl as a model drug was used
to
determine the mechanism of drug release from the system following the BP
basket method.
The dissolution rates of the wafer were determined in a small volume (10 mL
phosphate
buffer solution, pH 6.8) with a basket rotation speed at 50 rpm. At given
interval (e.g., 0.5, 1,

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56
2, 3, 4, 5, 7, 10 and 15 min), 0.5 mL of solution was sampled and replaced
with an equal
volume of fresh medium. The drug released was measured by HPLC.
[000193] The mobile phase was methanol: 0.4% phosphoric acld (50: 50, v/v, pH
2.3) and
the flow rate was 1.2 ml/min at ambient temperature. The monitoring wavelength
was at 210
nm. The calibration curve for the concentrations 0,5-10 pg/mL (eight-point
calibration) was ,
linear [y--316668x+4675.7, (r=0.9999), y representing the peak area of
fentanyl and x the
concentration of the samples]. The assay standard curve is shown in Figure 32.
[000194] The prepared fentanyl wafer (batch 1003FEN) showed a weight variation
of
2.55%, and the mean percentage fentanyl content of the wafer was 91.32% (BP
standard for
uniformity content limits 85 to 115%). The average disintegration times were
less than 15
seconds; and the dissolution studies also indicated a fast release rate of
fentanyl. Almost
90% of fentanyl had dissolved in one minute. The dissolution profiles are
presented in
Figure 33.
[000195] The HPLC chromatograms of six dissolution samples of fentanyl wafers
were
collected and is shown in Figures 34 A to E (samples 1 to 3) and Figures 35 A
to J. (samples
4 to 6). The sampling of each test wafer was conducted at time of 0.5, 1, 5,
10, 15 and 20
minutes for dissolution samples 1 to 3, and at 1, 2, 3, 4, 5, 7 and 10 minutes
for dissolution
samples 4 to 6.
[000196] The fast dissolving dosage form Is a solid dispersion of drug into a
porous matrix.
After administration, this dosage form quickly disintegrates in the oral
cavity, and allows
rapidly dissolving drug to be absorbed by diffusion directly into the systemic
circulation, and
the first-pass effect is avoided. This invention has the potential to provide
an alternate route
of drug administration and results in lower rates of side effect.
Example 2
= [000197] A formulation of the present invention, in the form of a solid
dosage form (wafer)
containing ketamine, was prepared in accordance with the method and
Ingredients as set
= out below in Table 3:

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Table 3: Compositions of Ketamine Fast Dissolving Solid Dosage Form
(Strength equivalent of 25 mg of ketamine base)
Ingredient (BP/USP) Amount (g) % by weight
-
Sodium carbonate 1 1 0.07
Sodium 2 0,15
carboxymethylcellulose
Polyethylene glycol 2000 5 0.36
Glycine 1 0.07
Microcrystailine cellulose 2 0.15
Amylopectln 50 3,64
Kotemine _62.5 4.55
Lactose 100 7.28
Mannitol 150- 10,92
Purified water -1000 72.81
1000198] The dosage form wafers containing ketamine Were produced using the
method
of Example 1 above.
10001991 The following additional formulations were prepared by the method of
Example
1. Samples Ito 6 are based on the formulation described above (strength
equivalent of 25
mg ketamine base), with the addition of flavour andfor colour agents.
Sample 1. Additionally contained a flavour.
Ingredient Amount (g) % by weight
Sodium carbonate - 1 0.07
Sodium 2 0.14
carboxymelhylcellulose
Polyethylene glycol 2000 5 0,35
Orange flavour 10 0.71
Glycine 10 0.71
MIcrocrystailine cellulose 20 1.42
- Amylopectin 50 3.54
Ketamine 62.5 4.43
Lactose 100 7.09
Mannitol 150 10.63
Purified water 1000 70.90

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Sample 2. Additionally contained a flavour and a pH adjuster (citric acid).
Ingredient Amount (g) % by weight
Sodium carbonate 1 r 0.07
Sodium 2 0.14
corboxymethylcollulose
Cltric acid 5 - 0.35
Polyethylene glycol 2000 5 0.35
Mint flavour 10 0.71
Glycine 10 0.71
Microcrystalline cellulose 20 1.41
Amylopectin 50 3.63
Ketamine 62.50 - 4.42
Lactose 100 7.06
Mannitol 150 11,09
Purified water 1000 - 7= 0.66
Sample 3. Additionally contained a flavour and a colouring agent
Ingredient Amount (g) % by weight
FD & C red 0.1 - 0.01
Sodium carbonate 1 0= .07
Sodium 2 0= .14
carboxymethylcellulose
Polyethylene glycol 2000 - 5 0.35
Grape flavour 9.9 0.70
Glyclne 10 0= ,71
Microcrystaillne cellulose - 20 1.42
= Amylopectin 60 3.54
Katamine 62.5 - 4= .43
Lactose 100 7.09
Mannitol 150 - 110.43
P Lined water 1000 70.90

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'Sample 4. Additionally contained a flavour, a colouring agent and an
absorption enhancer
Ingredient Amount (g) % by weight
FD & C blue 0,1 0.01
4--
Sodium carbonate 1 0= .07
Sodium 2 0.14
carboxymethylcellulose
'13-Cyclodextrin 5 0.35
Polyethylene glycol 2000 5 0.35
Grape flavour .9_9 0.70
Gtrine = 10 0.71
Microcrystalline cellulose 20 1.41
Arnylopectin 50 3.53
Ketamine 62.5 4.42
Lactose 100 7.06
Mannitot 145 10.24
Purified water 1000 70.65
Sample 5. Additionally contained a colouring agent and a sweetener
ingredient Amount (g) % by weight
ED & C red 0.1 0.01
Sodium carbonate p.o7
Sodium 2 0.14
carboxymethylcellulose
Aspartame 5 0.35
Polyethylene glycol 2000 - 5 0.35
Cherry flavour 9,9 0= .70
Glyclne 10 0.71
MIcrocrystallIne cellulose 20 1= .41
Amylopectin 50 3= .53
Ketamine 62.5 4.42
Lactose - 100 7.06
MannitoI - 145 10.24
Purified water 1000 70.65

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Sample 6. Additionally contained a colouring agent and a pH adjuster
= Ingredient Amount (g) % by weight
FD &C red 0.1. 0.01
Sodium carbonate 1 0.07
Sodium carboxymethylcellulose 2 0.14
Sodium hydrogen carbonate 5 0.35
Polyethylene glycol 2000 5 0.35
Raspberry flavour 9.9 0.70
Glyoine 10 0.71
MicrocrystallIne cellulose 20 1.41
Amylopectin 50 3.53
= Ketamine 62.5 .. 4.42
Lactose 100 7.06
Mannitol - 145 10.24
Purified water 1000 70.65
[000200] Various strength of ketamine fast dissolving solid dosage form
(wafers) were
then prepared based on the formulation shown in Table 3 and prepared as set
out in
Example 1 above. The batch number and the ingredients are listed in Table 4.

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Table 4: KetaMine Compositions Used for Investigations
:Thatch 201103231c Batch 20110528 Batch 20110820 _
(strength equivalent of (strength equivalent of (strength equivalent of
25 mg ketamlne base) 25 mg ketamine base) 50 mg ketamine base)
Ingredient Amount (g) Amount (g) Amount (g)
Amytopectin 1.0 1,0 1.2
Mannttol 3.0 3.0 r 2.9
Lactose 2.0 2.0 1.9
Glycine - 0,2 0.2 0.3
Polyethylene glycol 0.1 0.1 0.1
2000
Sodlurn 0.04 0.04 0,04
Carboxymethyl-
cellulose
Sodium carbonate 0.02 0.02 0.05
Avicel 0,2 0.2 0.2
Active 1.250 ketamine (base) 1.250 ketamine (base) 2.50
ketamine (base)
pharmaceutical
ingredient
Purified water 40 40 40
= In vitro studies
[000201] The in vitro studies were to describe the physicochemical properties
of freeze-
dried ketamine (equivalent to 26 mg of ketamine base) fast dissolving solid
dosage form.
Uniformity of Welay
[000202] The uniformity of the weight of the ketamine wafers was tested as
provided In ,
Example 1. Twenty wafers from the formulations listed In Table 4 were
individually weighed,
and the average weight and relative standard deviation was calculated. All the
prepared
wafers from different formulations were within the accepted weight variation
of 0.25 to 2%.
Hardness
[000203] The hardness of the wafer was also tested in accordance with the
method given
In Example 1. The hardness values from different formulations ranged from 0.5
to 4.0 kg.
Batch 20110528 gave a hardness of 0.5 to 1.0 kg and this formulation was then
used in -
subsequent clinical trial. This formulation enables a fast dissolution rate
and allows for easy
handling.

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Friability
[000204] The strength of ketamine wafers was tested according the method of
Example 1.
A sample of 20 ketamine wafers had a percentage weight loss of between 8 to
20%.
Moisture Analysis
10002051 The moisture content of the ketamine wafers was analysed as provided
in
Example 1. The results showed that the residual moisture content was around
4%.
Scannino electron microscopic analysis
[0002061 Surface morphology and cross-section of selected wafer formulation
samples
were observed using the method provided in Example 1. The SEM images shown in
Figures
36 and 37 illustrate the highly porous nature of the ketamine containing
wafers for both
surface and the inner structures.
Powder X-ray diffractionIXRD)
[000207] Powder X-ray diffraction experiments were performed using the method
of
Example 1.
[000206] The physical state of the materials in the ketamine containing wafers
was evident
in the X-ray diffraction spectra. Spectra for three different formulations
prepared in
accordance with Table 4 are shown in Figures 38, 39 and 40. It was observed
that all the
powder patterns of wafers prepared were dominated by intense scattering peaks
approximately located at 2-theta of 9.58 , 19, 68 and 20.05 . which
Indicating a crystalline
nature of the excipient AVICel. This finding was also supported by the data
generated from
the SEM. Indeed, the excipients used In the formulations, such as glycine,
lactose, mannitoI
and microcrystalline cellulose are crystalline In nature. However, all became
amorphous
after freeze-drying.
Disintegration and Dissolution Analysis
[000209] Disintegration and dissolution tests Were carried out according to
Example 1.
[000210] For. the disintegration test, It was shown that the ketamine
containing wafers of
the present invention were able to completely dissolve in about 15 seconds and
did not
leave behind any residue.
For the dissolution testing, a wafer from Batch 20110528 containing ketamine
was used to
determine the level of drug release from the formulation. The dissolution
rates of the
ketamine wafer were determined in a large volume (200 mL phosphate buffer
solUtion, 26

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mM, pH 6.8) with a basket rotation speed at 76 rpm, At given intervals (e.g.,
1, 3, 5, 7, 10,
15, 20 and 30 min), 1.0 mL of solution was sampled and replaced with an equal
volume of
fresh medium. The drug released was measured by HPLC with a C18 column (150 x
4.6
mm, 5 pm), a mobile phase of 15% v/v acetonitrile in 85% of 50 mM H3PO4, 20mM
triethylamine HC1 (pH 3.00) and the flow rate was 1.5 mi/min at ambient
temperature. The
monitoring wavelength was at 210 nm. The HPLC chromatograms of dissolution
ketamine
wafer were shown In Figures 41 to 48.
[0002111 The calibration curve for the concentrations 5 to 100 p.g/mL (seven-
point
calibration) was linear [Y=16225X+3328.9, (R2=1), Y representing the peak area
of
ketamine and X the concentration of the samples]. The assay standard curve is
shown in
Figure 49.
[000212] The prepared ketamine wafer (Batch 20110528) showed a weight
variation of
2.55%, and the mean percentage ketamine content of the wafer was 98.67% (HP
standard
for uniformity content limits 85 to 115%). The HPLC chromatogram is shown in
Figure 50.
[0002131 The average disintegration times (BP disintegration apparatus) were
less than 5
seconds; and the dissolution studies also indicated a fast release rate of
ketamine. Almost
95% of ketamine had dissolved within one minute. This may Indicate the
changing of
ketamine crystal form In the wafer, which was also evident in the X-ray. The X-
ray spectrum
pointed to an amorphization of ketamine during the freeze-drying process.
[0002143 The dissolution profiles are presented in Figure 51.
10002151 The ketamine wafer is a solid dispersion of ketamine hydrochloride
into a porous
matrix. After administration, this dosage form is quickly disintegrates in the
oral cavity, and.
allows rapidly dissolving ketamine to be absorbed by diffusion directly into
the systemic
circulation, and the first-pass effect is avoided. This invention has the
potential to provide an
alternate route of drug administration and results in lower rates of side
effect.
= in vivo studies
(0002161 The aims of the in vivo study were to 1) investigate the
pharmacokinetic profile
of ketamine wafer (equivalent to 25 mg a ketamine base, Batch Number: 20110528
in Table
4); 2) determine the absolute bioavallability of a single 25 mg sublingual
dose of ketamine
wafer; and 3) evaluate the clinical characteristics and acceptability of the
present invention
using modified Liked, and Bond and Lacier scales.

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Ethical Approval
[000217] The protocol was approved by the Royal Adelaide Human Research Ethics
Committee. This trial was registered with the Australian Therapeutic Goods
Administration
under the Clinical Trial Notification Scheme (CTN: 2011/0292).
Study Subiects
[000218] All volunteers gave their written informed consent on an approved
subject
consent form, prior to undergoing trial procedures. Subjects included in the
study were
between 19 to 41 years of age, had a body mass index between 22 and 30kg/m2,
had no
history of or showed no presence of drug or alcohol dependence or abuse, had
normal
findings on the clinical history and laboratory testing, were free of
sublingual or buccal
ulceration or disease, and had negative findings on HIV, hepatitis B and C
viral testing.
[000219] A total of eight healthy males who met the study inclusion and
exclusion criteria
were enrolled In this study.
Study Plan and Design
[000220] This was a single-centre (Pain and Anaesthesia Research Clinic, Royal
Adelaide
Hospital, Adelaide, SA 5005, Australia), randomized, open-label, single-dose,
two-treatment,
two-period, two-way crossover study. According to the randomization plan,
subjects were
divided into two groups, in a 1:1 ratio using a computer-generated table of
random numbers.
[000221] The volunteers received both a single 10 Mg intravenous (IV) dose of
ketamine
(diluted to 30 mL in saline and administered as an IV infusion over 30 min)
and a 25 mg
sublingual (SL) wafer dose of ketamine. The sequence of treatment periods was
balanced
and randomised. The wafer was administered by placing it under the tongue. The
volunteer
was requested to avoid swallowing for at least ten minutes, to minimize loss
of ketamine via
the oral route and hence through gut and liver metabolism (the first pass
effect). The total
study duration was four weeks, including a 14-day screening period and a seven-
day wash-
out period.
[000222] Measurements of pharmacokinetics, tolerability and safety were carded
out for
24 hours following both dosing occasions. The total residency period at the
Pain and
Anaesthesia Research Clinic was 28 hours in Period 1 and 29 hours in Period 2.
[000223] Blood samples (5 ml..) for quantification of ketamine concentration
were taken
following both IV and SL administration at pre dose (within 5 minutes of
scheduled dosing
time), 5, 10, 15, 30, 35 and 45 minutes, and at 1, 1.5, 2, 2.5, 3, 4, 6, 8,
12, and 24 hours post

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dose. Samples up to and including the 8 hour post-dose sample were to be
collected within
two minutes of nominal time, thereafter all post-dose samples were to be
collected within ten
minutes of nominal time. The actual blood collection time was recorded in the
source
documents. All deviations outside of the windows specified above were to be
documented as
protocol deviations. The total amount of blood to be taken throughout the
study duration was
approximately 275 mL.
10002241 After collection, the blood samples were immediately centrifuged at 4
C, 2000-
2500g for 15 minutes and the plasma extracted and placed into polypropylene
storage
tubes. The plasma was stored at -80 C 10 C until transfer to the
bioanalytical laboratory.
Pharmacokinetic Analysis
[000225] The analysis of the plasma concentrations of racemic ketamine was
performed
using a validated HPLC method with UV detection, with a lower limit of
quantification of 2
ng/mL and <20% bias and imprecision.
[000226] Standard non-compartmental analysis was used to derive
Pharmacokinetic
variables, except for C, tmax and tem, which were taken as observations from
the plasma
concentration time profile of eaCh subject. Actual times were used when
reporting tmx. The
terminal rate constant () was estimated by log-linear regression, I.e. the
slope of the
natural log concentration vs. time curve where = -1'" slope. The linear
regression in the
terminal phase used the last three to six data points, at a minimum three
points. The terminal
t% was calculated as t ln(2) I Xz.
[0002271 The area under the plasma concentration time curve to the last
quantifiable
plasma concentration (AUCIõ,) was obtained using the linear up and log down
method and
extrapolated to infinity with CIõt/A, (last quantifiable plasma concentration
divided by ),.,) to
obtain the total AUC, AUCNF. The extrapolated portion of the AUC, AUCextr, was
obtained by
(1-AUCH9a/AUCINF) 100. The total area under the first moment curve, AUMCINF,
was
calculated in a similar manner to AUCINF and MRT was obtained as AUMCINF/AUCNF
correcting mean residence time (MRTiy.) for the duration of the 30 minute IV
infusion.
Clearance (CL) was calculated as dose/AUCINF for IV administration and in the
same way for
the sublingual dose. The clearance for a non-1V route is expressed as CL/F
i.e. a ratio of
clearance and bioay.ailability as the latter is unknown. The volume of
distribution, Nix, was
calculated as CLAt. The MAT for the sublingual administration was obtained as
the
difference between the MRT for the two routes of administration as, MRTsc
MRT/v. The
bioavallability (F) of ketamine was calculated as the ratio of the dose
adjusted AUCier
following 1V and sublingual dosing according to AUCsi/AUCiv * doseN/dosesL=

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Safety and Tolera ilitv
[000228] Safety assessments included scheduled adverse event (AE) probes,
spontaneous AE reporting, routine laboratory investigations, 12-lead
electrocardiograms
(ECGs) and vital sign evaluation during a 24 hour period from start of dosing.
A full physical
examination was performed before the first dosing occasion and 24 hours after
the second
dosing occasion.
[000229] Local tolerability was assessed, by using Liked scales, at pre dose,
5, 10, 15, 30
and 45 minutes and one hour post dose administration. Modified Bond and Lader
scales to
assess sedation and altered perception, by using the three factors
"alertness",
"contentedness" and "calmness", were performed at pre dose, 30 minutes post
dose and at
hours 1, 1.5, 2, 2.5, 3, 4, 6, 8, 12, and 24 hours post dose administration.
Statistical Analysis
[000230] Standard summary statistics were computed by treatment for each
pharmacokinetic variable. The 90% confidence interval (CI) was calculated for
the
bioava
RESULTS
[000231] The individual values and summary statistics for volunteer
characteristics are
reported in Table 5.

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Table 5: Subject Demographics
Subject
Age Body weight Height BMI
Randomization
(years) (kg) (cm) (m2)
No.
1 19 74.6 184.0 22,0
2 31 100.0 183.2 29.9
3 23 77.0 173.0 25.7
4 19 74,7 168.0 26.4
41 87.8 . 183.5 26.1
6 20 85.0 183.0 25.4
7 21 79.1 185.0 23.1
8 25 108.5 191.0 30.0
8 8 8 8
Mean (SD) 25 (7.6) 85.8 (12.49) 181.3 (7.29) 26.1 (2.83)
Min-Max 19-41 74.6-108.5 168.0-191.0 22.0-30.0
Plasma concentrations of racemIc (RS) Ketamine
(0002321 The geometric mean (gõ,õ) with an overlay of Individual RS ketamine
plasma
concentrations for all subjects following IV administration for the entire
sampling period is
depicted in Figure 52. For clarity, the first 12 hours following dosing are
shown separately in
Figure 53. The geometric mean with an overlay of individual RS ketamine plasma
concentrations for all subjects' for the entire sampling period following SL
administration are
shown in Figure 54 arid the first 12 hours are shown in Figure 55.
[000233j The IV and SL plasma concentration time curves were similar in shape,
except
for four subjects having 2-3 peaks for the SL route. Following Cm,
concentrations declined
biphasically for both IV and SL although the trend was more prominent for IV,
[000234] The first quantifiable concentration following both IV and SL dosing
was at five
minutes for all subjects, which indicates a fast absorption for the SL dose.
Plasma
concentrations were below limit of quantification in six subjects at 24 hours
and in one
subject at 12 hours for SL dosing. Following IV dosing, all subjects had
quantifiable levels at
12 hours and four subjects at 24 hours.
[0002351 Following IV dosing, Cir,õ occurred at the end of the infusion in all
but one
subject (No.6), where the C was observed in the sample taken five minutes
after the and
of the 30 minutes infusion.

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[000236] For the SL dose, the median time of the main peak i.e. tam, was 0,75
hour with
the earliest peak detected at 0.26 hour and the latest at 1 hour following
dosing. Subjects 4,
6, 6 and 7 had multiple minor peaks in their plasma concentration time profile
observed
during the first three hours following dose administration. Individual trim
values are shown in
Figure 56.
[000237) Table 6 presents individual estimates and summary statistics for the
main
pharmacokinetic variables. Individual AUCII,IF values for both routes of
administration are
shown in Figure 57. The extrapolated portion of the AUC, AUCeinr, was very
small for both
routes of administration, which is Indicative of a high quality in the
estimation of the AUC
values. For IV, the AUC,,,tr was 3-7% and for SL it was 2-9%.
[000238] Individual estimates of CL for the IV route are presented in Figure
58. Following
SL dosing the CL is confounded by F, and hence cannot be compared to the
values
obtained following IV dosing. Median CL for IV dosing was 37.7 IJhr.
10002391 The terminal half-lives following IV and SL dosing were comparable,
with
medians of 4.6 and 3.4 hours, respectively. Similar half-lives for the IV and
SL routes
indicates that the absorption is fast, or else the slower absorption half-life
would be
governing the terminal phase of the plasma concentration time curve and hence
show a
considerably longer half-life than IV administration. Individual values for
both routes of
administration are provided in Figure 59.
=

Table 6: Individual pharmacokinetic variables and summary statistics of RS
ketamine foilowing administration of 10mg as a 30 minute IV o
w
infusion and 25 mg St, to eight healthy volunteers.
71
,
=
LA,
-4
Subject Croaxn tramp/ Cons.03. Wool. AUCINF JV AU CINF_SI.
CL V. t111,1V tinA, Go4
!A
(igimL) (fir) (ngimL) (fir) (hr*rigfml.) (heng/mL) (1-/Plr) (L)
010 (hi)
i 226.68 0.5 88.76 0.58 282.73 202.89 35.37 126 2.6 2.9
2 16326 0.5 12828 0.25 243.24 162.52 41.11 158 2.7 1.8
_
3 190.27 0.5 78.72 0.75 254,69 184-28 39.28 233 5,0 32
, 4 124-24 0.5 6024 1 270.02 203.47 37.03 253 4.7
5.8 n
120.38 0.5 50.02 0.75 289.22 171.90 34.68
300 6.0 3,5 0
N)
co
co
6 10t88 0$ 76.12 1 299.44 211.33 33.49 164
3.4 2.3 cn
ul
.
-1
7 83.18 0.5 51.79 1 261.00 186.14 33.31 3,85
7.0 4,8 1 ..:1?= L,
-
iv
0
1-,
8 81.12 0.52 61.17 0.5 167.21 161.64 59.81 376
4.3 8.1 . Lri
1
0
L...)
1
Gmean = 128.07 0.50 71.08 0.76 254.98 184.65 39.22
237 4,5 3.4 ui
0
81,12- 0.50- 50.02- 0.25- 16721- 161.64- 33.40- 126-
2.5- 1.8-
NTin-Max
.
226.68 0,60 128.28 1.09 299.44 211,33 59.80 385
7.0 5.5
CV (e) 16 NA 14 21 8 4 s 18 16 17
a gmean is provided for all variables except for tn... and ke %tem
medians are shown
"d
NA Not applicable
n
-,
c4
t.a
=
r.74'
'--
=
w
u,
sz
44

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=
Bioavailabilitv and Absorption
[000240] in a majority of subjects, the SL wafer dissolved within 30 seconds
to one
minute.
[000241] Individual estimates of bioavallability are shown in Figure 60 and
individual
bioavailability and MAT (mean absorption time) values together with summary
statistics are
provided in Table 7. Subject No.8 had a noticeably higher bioavallability,
38%, than others.
This subject was not markedly different in comparison to other subjects, apart
from having
the highest extrapolated areas, 9% for SL and 7% for IV, and a double peak for
the SL dose.
The median and 90% CI [lower, upper] for bioavailability was 29 [27, 31] %,
showing the
very low inter subject variability.
Table 7: Individual (Subject=randomiza(ion number), median, minimum and
maximum
of RS ketamine bioavailability (F) and mean absorption time (MAT) following
SL administration of 25 mg to eight healthy volunteers.
Subject F (%) MAT (hr)
1 28 1.1
2 27 -0.83
3 29 -1.1
4 30 0.86
6 23 -1.1
6 29 -0.56
7 29 0.20
8 38 0.64
Median 29 -0.18
Min-Max 23-38 -1.1 ¨ 1,1
90%Cl [27, 31] NA*
[lower, upper]
* Not applicable
[000242] The MAT represents the average time molecules of ketamine take to
pass from
the administration site, SL space, to the systemic circulation. The individual
MRT values
were comparable for the two routes of administration, median of 3.9 for IV and
3.8 hours for
SL, indicating a fast absorption. A small difference, i.e. a small MAT,
between the MRT for IV
and SL indicates fast absorption. Taking the difference between two similar
values might

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produce negative values, as is seen in some of the MAT values, due to
naturally occurring
variability.
[0002431 In summary, the PK of the SL wafer is characterised by fast
absorption and low
variability in bioavallabllity. This taken together with low variability In
clearance translates Into
low variability in exposure. Low variability allows for increased accuracy In
predicting total
exposure and hence pharmacological effect of the SL wafer, which might be
expected to
increase its utility In the clinical setting.
Pharmacodynamic Results
Bond and Lader Mood Rating Scales
10002441 The Bond and Lacier scales comprise a total of 16 100-mm lines
anchored at
either end by antonyms. Participants marked their current subjective state
between the
antonyms on the line. Each line was scored as millimetres to the mark from the
negative
antonym. From the resultant scores, three measures derived by factor analysis
were
isolated. These have been described by Bond and Leder as representing the
following:
= Factor1: "alertness" (represented by lines anchored by alert-drowsy,
attentive-
dreamy, lethargic-energetic, muzzy-clearheaded, well-coordinated-clumsy,
mentally
slow-quick witted, strong-feeble, interested-bored, incompetent-proficient);
= Factor 2: "contentedness" (contented-discontented, troubled-tranquil,
happy-sad,
antagonistic-friendly, withdrawn-sociable) and
= Factor 3: "calmness" (calm-excited, tense-relaxed); Scores for each
factor represent
the unweIghted average number of millimetres (maximum 100 mm) from the
negative
antonym for the Individual scales contributing to the factor.
Hence the maximum score for Factor 1 is 900; for Factor 2, 500 and for Factor
3, 200.
[0002451 The mood rating scales showed no clear trends for effects. Following
SL dosing
the Factors "alertness" and "contentedness" were fluctuating around the pre-
dose level
throughout the 24 hr observation period while "calmness" showed an initial
decrease during
the first hour after dosing, likely due to excitement caused by dosing and the
local tolerability
observations during the first 30760 minutes, followed by a steady increase and
full recovery
by 2.5 hr post dose. The shapes of the profiles following IV dosing were
comparable to that
of SL dosing. Profiles of mean (SD) values for each Factor of the mood rating
scales
following IV and SL dosing are depicted in Figure 61 and Figure 62,
respectively.
Modified Like it Scales of Local Tolerability
[000246) Modified Liked scales were used to assess the following symptoms:
cheek
irritation; burning sensation; bitterness and nausea. As expected, values were
generally zero

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for all values following IV administration although there were sporadic values
of one or two.
Following SL administration, values were generally zero or sporadically one or
two for _
"cheek irritation" and were similar for "burning sensation" although there was
a single value
of three reported at 10 minutes by subject 3. For "nausea", values showed the
same trend as
for IV with mainly zero values but sporadic values of one or two. However
values for
"bitterness" were different from IV: all subjects reported non-zero post dose
values although
the peak ranged from 1-9 with One subject each reporting a peak of one and
three, with the
remainder being five or greater. The highest value was at five minutes in four
subjects; at 10
minutes in two subjects; 15 minutes in one subject and one subject reported
values of nine
at both five and 10 minutes. All values had returned to zero by one hour
(Figure 63),
[000247] There were no clinically relevant changes or trends for abnormalities
in ECG,
vital signs, haematology, clinical chemistry or urinalysis.
[000248] In summary, the sublingual wafer formulation of ketamine has been
developed
as a potential adjunct in acute and chronic pain management, and other
disorders. The
median bioavailability from this example Is 29% with very low inter subject
variability, which
is favourable for a relatively narrow therapeutic Index drug such as ketamine.
Low variability
also increases the utility of the wafer in terms of reproducible exposure and
hence analgesic
effect. Ketamine administered as a 25 mg sublingual wafer to healthy
volunteers, was safe
and well tolerated with the exception of mild and transient CNS-type symptoms,
as expected
based on the existing clinical experience of ketamine. The local tolerability
was excellent,
and any local irritant effects are expected to be mild and resolve within 30-
60 minutes
following dosing.
Example 3
[000249] A formulation of the present invention, in the form of a solid dosage
form (wafer)
containing sildenafil, was prepared in accordance with the method and
ingredients as set out
below in Table 8:

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Table 8: Compositions of Sildenafif Fast Dissolving Solid Dosage Form
(Strength equivalent of 25 mg of sildenafil base).
Ingredient Amount (g) % by weight
Sodium carbonate BP/USP 1 0.07
Sodium 2 . 0.14
carboxymethylcellulose
BPNSP
Polyethylene glycol 2000 5 0.34 =
BP/USP
= Glydne BP/USP 10 0.68
Microcrystalline cellulose 10 0.68
BP/USP
Citric add BPNSP 10 0.88
Amylopectin BP/USP 50 3.42
Lactose BP/USP 100 6,84
Mannitoll3P/USP 150 = 10.25
Sildenafil BP/USP 125 8.54
Purified water BP/USP 1000 68.35
[000250] The dosage form wafers containing sifdenafil (25 mg) were produced
using the
method of Example 1 above.
[000251] The following additional formulations were prepared by the method as
set out
above. Essentially Samples 1 to 6 are based on the formulation described
above, with the
addition of flavour and/or colour agents.
=
= =

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Sample 1. Additionally contained a flavour.
Ingredient Amount (g) % by weight
Sodium carbonate 1 0.07
Sodium 2 0.15
carboXymethylcellulose
Polyethylene glycol 2000 5 0.37
Orange flavour 10 0.74
Glycine 10 0.74 -
¨
'Citric acid 10 0.74
MIcrocrystallIne cellulose 20 1.47
Amy10/Actin 50 3.68
Lactose 100 6.84
Mannitol 150 10.25
Sildenafil BP/USP 125 8.54
Purified water 1000 66.41
Sample 2. Additionally contained a flavour and a pH adjuster (citric acid)
Ingredient Amount (g) % by weight
Sodium carbonate 1 0.07
Sodium 2 0.15
= carboxymethylcellulose
Polyethylene glycol 2000 5 0.37
Citric acid 10 0.74
Mint flavour 10 0.74
Glydne 10 0.74
Microorystalline cellulose 20 1.47
Amylopectin 60 3.68
Lactose 100 6.84
Mannitol 150 10,25
= Sildenafil BP/USP 125
Purified water 1000 67.15
=

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=
Sample 3. Additionally contained flavour and a colouring agent
Ingredient Amount (g) % by weight
FD & C red 0.1 0.01
Sodium carbonate 1 0.07
Sodium 2 0.15
carboxymethylcellulose
Polyethylene glycol 2000 5 0.37 '
... _______________________________________________________
Grape flavour 9.9 0.73
Glycine 10 0.74
Microcrystalline cellulose 20 1_48
Amylopeetin 50 3.71
Lactose 100 6.84
Mannttol 150 10.25
Stldenafil DP/USP 126 8.54
Purified water 1000 , 67.11
Sample 4. Additionally contained a flavour, a colouring agent and an
absorption enhancer
Ingredient Amount (g) % by weight
FD & C blue 0.1 0.01
Sodium carbonate 1 0.07
Sodium 2 0.16
carboxymethylcellulose
..... _____________________________________________________
p=Cyclodextrin 5 0.37
_ _________________________________________________________
Polyethylene glycol 2000 5 0.37
,
Grape flavour 9.9 0.73
Glyoine 10 0.74
Citric acid 10 0.74
Miorocrystalline cellulose 20 1.47
Amylopectin 50 3.71
Lactose 100 6.04
Mannitol 150 10.25
Sildenafil BP/USP 125 8.64
Purified water ' 1000 66.01
,
=

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Sample 5, Additionally contained a colouring agent and a sweetener
Ingredient Amount (g) % by weight
FD & C red 0.1 0.01
Sodium carbonate 1 0.07
Sodium 2 0.15
carboxymothylcellulose
Aspartame 5 0.37
Polyethylene glycol 2000 5 0.37
Cherry flavour 9.9 0,73
Glycine 10 0.74
Microcrystalline cellulose 20 1.48
Amylopectin 50 3.71
Lactose 100 6.84
Mannitol 150 10.25
Sildenafil BP/USP 125 8.54
Purified water 1000 66.74
Sample 6. Additionally contained a colouring agent and a pH adjuster
Ingredient Amount (g) % by weight
ED & C red 0.1 0.01
Sodium carbonate 1 0.07
Sodium 2 0.15
carboxymethylcellulose
Sodium hydrogen 5 0.37
carbonate
Polyethylene glycol 2000 5 0.37
Raspberry flavour 9.9 0.73
Glycine 10 0.74
Microcrystalline cellulose 20 1.48
Amylopectin 50 3.71
Lactose 100 8.84
Mannitol 150 10.25
Sildenafil 1313/USP . 125 8.54
Purified water 1000 86.74

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[000252] Various batches of slidenafil fast dissolving solid dosage form
wafers were then
prepared based on the formulation shown In Table 8 and prepared as set out in
Example 1
above. The batch number and the ingredients are listed in Table 9.
Table 9: Compositions of Slidenafil Formulations Used for Investigations
(Strength equivalent of 25 mg of sildenafil base)
_
Batch Batch Batch r Batch Batch
0715015 0715028 0820A 0820B 20120628
Ingredient -
Amount (g) Amount (g) Amount (g) Amount (g) Amount (g)
k
Amylopectin 1.0 1.0 1.0 0.00 . to
..._
Mannitol 3.0 3.0 3.0 3.0 3.0
_
Lactose 2.0 2.0 2.0 2,0 2.0
. Glycine 0.2 0.2 0.5 0.3 0.2
_
PEG 2000 0.1 0.1 0.1 0.1 0.1
_
Sodium Carboxymethyl- 0.04 0.04 0.04 0.04 0.04
cellulose
Sodium Carbonate 0 0.02 0 0 0.02
_
Starch 1.0 0 0 0 0
_
-Citric add 0 . 0 0 0 0.2
- Avicel 0.2 02 0.00 -0.2 ' 0.2
Active pharmaceutical 0 0 0 0 2.6
Ingredient . sildenafil
(base)
_
Purified water 40 40 40 40 40
= In
Vitro studies ,
Uniformity of Weight
(000253) The uniformity of the weight of the sildenafil wafer was tested as
provided in
Example 1. Twenty wafers from the formulations listed in Table 9 were
individually weighed,
and the average weight and relative standard deviation was calculated. All the
prepared
wafers from different formulations were within the accepted weight variation
of 0.25 to 2%.
Hardness ,
[000254) The hardness of the wafer was also tested in accordance with the
method given
In Example 1. The hardness values from different formulations ranged from 0.5
to 4.0 Kg.
Batch 20120628 gave a hardness of the wafer at 0.5 to 1.0 kg and this
formulation was used
=

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in the subsequent clinical trial This formulation enables a fast dissolution
rate and allows for
easy handling.
Friability
[000255) The strength of sildenafil wafers (including their ability to be
reduced from a solid
substance into smaller pieces) was measured in accordance with the method
given in
Example 1. A sample of 20 sildenafll wafers had a percentage weight loss of
between 8 to
20%,
Moisture Analysis
[000256] The moisture content of the sildenafil wafers was analysed as
provided in
Example 1. The results showed that the residual moisture content was around
4%.
Scanning electron microscpsic analysis
[000257] Surface morphology and cross-section of selected wafer formulation
samples
were observed using the method provided in Example 1. The SEM Images shown in
Figures
64 and 65 show clear morphological differences between blank and sildenafil
wafers.
Powder X-ray diffraction (XRD)
[000258] Powder X-ray diffraction experiments were performed using the method
of
Example 1.
[000259] The physical state of the materials in the sildenafil wafers was
evident in the X-
ray diffraction spectra. Spectra for three different formulations as prepared
in accordance
with Table 9 are shown in Figures 66, 67 and 68. It was observed that all the
powder
patterns of wafers prepared were dominated by Intense scattering peaks
approximately
located at 2-theta of 9.58 , 19, 68 and 20.05 , which indicating a
crystalline nature of the
excipient Avicel. This finding was also supported by the data generated from
the SEM.
Indeed, the excipients used in the formulations, such as glycine, lactose,
mannitol and
microcrystaliine cellulose are crystalline in nature. However, it seemed all
became
amorphous after freeze-drying.
Disintegration and Dissolution Analysis
[000260] Disintegration and dissolution tests were carried out according to
Example1 .
[000261] For the disintegration test, it was shown that the sildenaffl
containing wafers of
the present invention were able to completely dissolve In about 15 seconds and
did not
leave behind any residue.

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For the dissolution testing:
[000262] Dissolution tests were carried out using Apparatus I (BP 2009, Basket
apparatus). The Erweka dissolution apparatus (Hesenstamm, Germany) was used
for both
tests. The temperature of the medium was kept at 37 - 0.5 C. A wafer (Batch
20120628)
containing sildenafil was used to determine the level of drug release from the
formulation.
The dissolution rates of the sildenafil wafer were determined using the method
given in
Example 2
[000263] The calibration curve for the concentrations 5 to 100 pg/mL of
sildenafil (seven-
point calibration) was linear [Y=32.973X-36538, (rrr-0.9999), Y representing
the peak area of
sildenafil and X the concentration of the samples]. The assay standard curve
is shown in
Figure 77. =
[000264] The prepared sildenafil wafer (Batch 20120628) showed a weight
variation of
2.55%, and the mean percentage sildenafil content of the wafer was 98.67% (BP
standard
for uniformity content limits 85 to 115%). The average disintegration times
(BP disintegration
apparatus) were less than 5 seconds; and the dissolution studies also
indicated a fast
release rate of sildenafil. Almost 95% of siiderrafil had dissolved within one
minute. This
may indicate the changing of sildenafil crystal form In the wafer, which was
also evident in
= the X-ray. The X-ray spectrum pointed to an amorphization of sildenafil
during the freeze-
drying process.
[000265] The dissolution profiles are presented in Figure 78.
[000266] The sildenafil wafer is a solid dispersion of sildenafil
hydrochloride Into a porous
matrix. After administration, this dosage form quickly disintegrates in oral
cavity, and allows
the rapidly dissolving sildenafil to be absorbed by diffusion directly into
the systemic
circulation, and the first-pass effect is avoided. This invention has the
potential to provide an
alternate route of drug administration and results in lower rates of side
effect.
Example 4
[000267] A formulation of the present invention , In the form of a solid
dosage form (wafer)
containing adrenaline, was prepared in accordance with the method and
ingredients as set
out below in Table 10:

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Table 10: Composition of Adrenaline Fast Dissolving Solid Dosage Form
(Strength equivalent of 40 mg of adrenaline base)
Ingredient_ _ _ % by weight
Sodium carbonate 1 0.07
Sodium 2 0.15
carboxymethylcellulose
Polyethylene glycol 2000 _ 5 0.36
Glycine 1 0.07
MIcrocrystalline cellulose 2 0.16
Amylopectin 50 3.64
Adrenaline (Base) 100 728
Lactose 100 7.28
Mannitol 150 10.92
Purified water 1000 70.08
(0002681 The fast dissolving dosage form (wafer) containing 'adrenaline was
produced
using the method of Example 1 above.
10002691 The following additional formulations were prepared by the method as
set out
above. Samples 1 to 6 are based on the formulation described above (strength
equivalent of
40 mg adrenaline base), with the addition of flavour and/or colour agents.

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Sample 1, Additionally contained a flavour
_Ingredient Amount (g) % by weight
Sodium carbonate 1 0.07
Sodium 2 0.14
carboxymethylcellulose
Polyethylene glycol 2000 6 0.35
Orange flavour 10 0.71
Glycine 10 0.71
Microcrystalline cellulose 20 1.42
Amylopectin 50 3.64
Adrenaline (Base) 100 7.09
Lactose 100 7.09
Mannitol 160 10.63
Purified water 1000 68,26
Sample 2. Additional contained a flavour and a pH adjuster (citric acid).
_ Ingredient Amount (g) % by weight
Sodium carbonate 1 0.07'
Sodium 2 0.14 =
carboxymethylcellulose
Citric acid . 6 0,36
Polyethylene glycol 2000 5 0.35
Mint flavour 10 0.71
Glycine 10 0.71
Microcrystalline cellulose 20 _ 1.41
Amylopectin 50 3.63
Adrenaline (Base) 100 7.06
Lactose 100 7.06
Mannitol 160 11.09
Purified water 1000 87.52

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Sample 3. Additionally contained flavour and a colouring agent
Ingredient Amount (%) % by weight
FD & C red 0.1 0.01
Sodium carbonate 1 _0.07'
Sodium 2 0.14
carboxymethylcellulose
Polyethylene glycol 2000 5 0.35
Grape flavour 9.9 - 0.70
Glycine 10 0.71
MIcrocrys ta Illne cellulose 20 1.42
Amylopectin 50 154
Adrenaline (Base) 100 7.09
Lactose 100 7.09
MannItol = 150 10.43
Purified water 1000 68.45
Sample 4. Additionally contained a flavour, a colouring agent and an
absorption enhancer
ingredient _ Amount (g) % by weight
ED eg'C blue 0.1 0.01
Sodium carbonate 1 _0.07
=
Sodium 2 0.14
carboxymethylcellulose
Glyceryl Trinitrate 28.57 2.00
Polyethylene glycol 2000 5 0.35
_Grape flavour 9_9 0.70
Glyclne 10 0.71
Microcrystalline cellulose 20 1_41
Amylopeotin 50 3.53
Adrenaline (Base) 100 7.06
Lactose 100 7.06
Mannitol 145 10.24
Purified water 1000 66.72

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Sample 5. Additionally contained a colouring agent and a sweetener =
Ingredient Amount (g) _% by weight
FD C red 0.1 0.01
Sodium carbonate 1 , 0.07
Sodium 2 0.14
carboxymethylcellulose
Aspartame 5 , 0.35
Polyethylene glycol ,2000 5 0.36
Cherry flavour 9.9 0.70
= Glyclne 10 0.71 =
Microcrystalline cellulose 20 1.41
. -
AmylopectIn 50 3.53
Adrenaline (Base) 100 7.06
, Lactose 100 7.08
Mannitol 145 10.24
Purified water 1000 68.42
Sample 6. Additionally 'contained a colouring agent and a pH adjuster
Ingredient Amount (g) % by weight
FD & C red 0.1 0.01
Sodium carbonate 1 0.07
Sodium carboxymethylcellulose 2 0.14
Sodium hydrogen carbonate 5 0.35
Polyethylene glycol 2000 5 0.35
Raspberry flavour 9.9 0.70
Glycine 10 0.71
Microcrystalline cellulose 20 ' 1.41
AmylopectIn 50 3.53
Adrenaline (Basel 100 7.06
Lactose 100 7.06
Mannitot 146 10.24
Purified water 1000 - 68.37 =

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[000270] Various strength of adrenaline bitartrate fast dissolving solid
dosage form (wafer)
were then prepared based on the formulation shown in Table 10 and prepared as
set out in
Example 1 above. The batch number and the ingredients are listed in Table 11.
Table 11: Adrenaline Compositions Used for investigations
Batch Batch Batch
(strength equivalent of (strength equivalent of (strength equivalent of
40 mg adrenaline base) 40 mg adrenaline base) 80 mg adrenaline
base)
Ingredient Amount (g) Amount (g) Amount (g)
Amylopectin 1.0 1.0 1.2
MannItol 3.0 3.0 2.9
Lactose 2.0 2.0 1.9
Glyclne 0.2 0.2 0.3
Polyethylene glycol 0.1 0.1 - 0.1
2000
Sodium 0.04 0.04 0.04
Carboxymethylcell
ulose
Sodium carbonate 0.02 0.02 ¨0.05
Avicel 0.2 0.2 0.2
Glycetyl Trinitrate 2.0 2.0 2.0
Adrenaline 3.838 3.638 5.458
bltartrate
Purified water 38 38 37
=

CA 02886573 2015-03-30
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PCT/IB2013/002594
gxampie 5,
A Phase I Pharmacokinetic and Bloavailability Study of a Sublingual Fentanyl
Wafer in
Healthy Volunteers
= Methods
Study Subtects
[000271] Healthy volunteers gave written informed consent on an approved
subject
consent form, before undergoing trial procedures. Subjects were included in
the study were
between 19 and 32 years of age, had a body mass index between 18 and 30 kg/m2,
had no
history or evidence of drug or alcohol dependence or abuse, had normal
findings after a
clinical history and laboratory testing, were free of SL (sublingual) or
buccal ulceration or
disease, and had negative findings for human immunodeficiency virus, hepatitis
B, and
hepatitis C viral testing.
[000272] Twenty-four volunteers who met the study inclusion and exclusion
criteria were
enrolled in this study. On the basis of an SD of the area under the curve
(AUC), values of
35% and a 20% difference being significant gives a power of 84% (cm. 0.05).
Study Desion
[000273] This was a single-centre (Linear Clinical Research Ltd., Perth,
Australia),
randomized, open-label, single-dose, 2-treatment, 2-period, 2-way crossover
study.
According to the randomization plan, subjects were divided into 2 groups, in a
1:1 ratio using
a computer-generated table of random numbers. The volunteers were given either
IV
fentanyl citrate or a sublingual fentanyl citrate wafer (based on Batch:
1003FEN formulation
of. Example 1; equivalent to 100 pg of fentany1). Each volunteer subsequently
received the
alternative route after a 7-day washout period.
1000274] The wafer was administered by placing it under the tongue. The
volunteer was
requested to avoid swallowing for as long as possible, at least for 10
minutes. A naltrexone
tablet (50 mg) was administered orally every 12 hours from before day 1 to the
evening of
day 2 (12 hours after the last fentanyl dose), so as to block any systemic
effects of fentanyl.
[000275] Before commencement of the study, a dedicated IV cannula was placed
in the
forearm for subsequent venous blood sampling. Blood samples (7 ml.) were taken
pre-dose
before the commencement of wafer administration and then at 2, 5, 10, 15, 20,
30, 45, 60,
120, 180, 360, 460, 600, 720, 960, and 1440 minutes after administration
commencement.

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For IV Infusion,, blood samples were taken at pre-dose, at 2 and 3 minutes
after
commencement, and at 6 minutes (end infusion), then at 7, 10, 15, 20, 25, 30,
45, 60, 120,
180, 360, 460, 600, 720, 840, 960, and 1440 minutes from infusion
commencement.
[000276] After collection, the blood samples were immediately centrifuged at 4
C, 2000 to
2600 g for 15 minutes and the plasma extracted and placed into polypropylene
storage
tubes. The plasma was stored at -80 C 10 C until transfer to the
bioanalytical laboratory.
Sample extracts were analysed on an API 4000 LC-MS/MS system (Applied
Biosystems,
Foster City, CA), preceded by a Shimadzu Prominence high-performance liquid
chromatography system with d5-fentanyl as the Internal standard. The assay had
a limit of
detection of 10 pg/mL. Precision was determined by duplicate analyses of
plasma containing
10, 40, and 400 pg/mL fentanyl. The results were precise to within 6.2%,
3.3%, and 1.7%
of the mean measured concentration values of 10, 40, and 400 pg/mL,
respectively, and
accurate to within 102%, 99.9%, and 101.4% of the nominal concentrations of
10, 40, and
400 pg/mL, respectively. At each concentration the number of replicates was 6.
Pharmacokinetic Analysis
[000277] The pharmacokinetic parameters were determined using Phoenix
WinNonlin
version 6.1 (Pharsight, A CertaraTm Company, St. Louis, MO). The
pharmacokinetic data
were Cm, t, AUCO 10 12, AUC0-1, AUCo.w, koi, and t112. First detectable
fentanyl plasma
concentration after SL administration (C) and the time to Clirst (twat) were
read directly from
the plasma fentanyl concentration-time curves. The terminal elimination rate
constant (kw)
was determined as the slope of the regression line of best fit to the
approximately log-linear
terminal elimination phase. All fitting was performed with unity weighting of
the data. The
terminal elimination half-life (t112) was obtained from kõ, and equaled In
2/k. The AUC0 to 12
and AUCo.i values were obtained using the trapezoidal rule. The extrapolation
to AUCc,,,,, was
calculated from AUCc,i +
Safety and Tolerability
[000278] Safety and tolerability were assessed by monitoring vital signs
(arterial blood
pressure and heart rate) after fentanyl administration. A full physical
examination was
performed before and 48 hours after drug administration. Laboratory tests and
a 12-lead
electrocardiogram were performed at baseline and completion of the study.
Adverse events
were assessed using direct observation, spontaneous reporting, and nonspecific
questioning.

CA 02886573 2015-03-30
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Statistical Analysis =
[000279] Summary statistics were computed by treatment of each pharmacokinetic
parameter. Sioavailability of St. fentanyl was determined separately for each
subject as the
ratio of Cmax, AUC0 ,õ j2, AUCpt, and AUCo...õ for SL administration In
comparison with IV
administration_ Overall bioavailability was estimated as the back-transform of
the difference
between treatments for log-transformed Cm, AUC0 to 121 AUCm, and AUCG., values
using a
linear model with terms for treatment, period, sequence, and subject within
sequence_ The
90% confidence interval (Cl) was also calculated, and P values <0,05 were
considered
statistically significant. All analyses Were conducted using SAS version 9.2
(SAS Institute
Inc., 2008). Differences in formulations were evaluated using Student t tests.
= Results
[000280] Twenty-four patients were randomized, 12 to the SL:IV sequence and 12
to the
IV:SL sequence. Two volunteers did not complete the SL or the 1V
administration arm of the
study and were eliminated from all analyses. The volunteer characteristics are
reported in
Figure 79.
Ph a rrnacokinetic Results
[000281] Mean plasma ( SM) fentanyl concentration versus time curves for the
IV and
SL routes are shown in Figure 80. Individual subject plasma concentration
profiles are
shown for the SL route in Figure 81. The mean values ( 1 SD) for the plasma
pharmacokinetic parameters Cmax. Grum AUC01012, AUC0.1, and AUC,,,õ for
fentanyi are shown
In Figure 82. The first detectable plasma fentanyl concentration (C1ws1),
after SL
administration, was observed between 2 and 10 minutes after administration.
The
cumulative percentage of the 22 volunteers with trim at 2, 5, and 10 minutes
and their mean .
plasma fentanyl concentration (CrNsi) were 12.5% (32.4 pg/mL), 62.6% (30.7
pg/mL), and
100.0% (49.0 pg/mL), respectively.
[000282] The mean time to peak plasma concentrations (t) after commencing IV
and SL
administration was 0.12 hour and 0.92 hour, respectively (P < 0.0001) (Figure
82). The
mean ( SD) terminal half-life (t112) for IV and SL administration was 13.07 *
3,00 hours and
12.49 5.24 hours, respectively (P 0.889). The mean ( SD) terminal
elimination rate
constant (k,o) for IV and SL administration was 0.055 0.012 VI and 0.064
0.025 WI,
respectively (A 0.317).
1000283) Bloavallability was assessed by the percentage ratios of 'SUN for
AUC0 to 12>
AUC04, and AtIC0_,., values. The mean hioavallability of SL fentanyl was
estimated to be

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72.1% (Cl, 65.3% to 79.6%) from AUC0 to 12, and 73.2% (Cl, 66.3% to 80.9%)
from AUCat.
Absolute bloavallability was 78.9% (Cl, 61.1% to 121.7%) on the basis of the
AUCo.., values.
[000284] The Cmax of SL fentanyl was 18.8% (Cl, 14.4% to 24.6%) of the IV
administration
value, with the average time to maximum concentration being 0.9 hour. For IV
administration, Cmõõ generally occurred at the end of the infusion, with a
rapid reduction over
the half hour immediately post-dose. From approximately 2 hours post-dose, the
mean
concentration¨time profiles were similar for the 2 modes of administration.
Tolerability
(0002851 All reported adverse events were mild to moderate. The mean ( SD)
time for the
wafer to dissolve in the SL pouch was 73 76 seconds.
[000286] This study was designed as a phase I study to determine the basic
pharmacokinetic parameters of a recently developed rapidly dissolving fentanyl
wafer. It also
collected some data on subject acceptance of the product.
10002871 It was found that the Cmax and tom values for the SL fentanyl (100
Ilg) wafer were
comparable (Figure 83) to data reported from a previously studied SL fentanyl
(100 pg)
tablet. The Cm and tõ values provide an indication of the rate of absorption
of drugs. The
wafer has similar Cõ, tõ, and AUG values, in comparison with the SL tablet (P
= 0.573,
0.331, and 0.103, respectively); no absolute bioavailability data were
available for the SL
tablet. It was noted that the SL tablet was evaluated in cancer patients over
a 10-hour
collection period, which causes different tv2 values of 6.1 and 12.5 hours for
the tablet and
wafer, respectively (P = 0.0013).
[000288] After SL administration, rapid absorption of fentanyl was evidenced
by detectable
plasma concentrations within 2 to 10 minutes (tom), occurring in most cases
within 5 minutes.
The wafer formulation had a Crum similar to that of the SL tablet. This
reflects fentanyl's high
permeability into the rich blood-flow (and good venous outflow) of the SL
mucosa, which
bypasses the hepatic 'first-pase effect. The SL mucosa (100 to 200 pm) is
thicker than the
nasal mucosa (40 to 80 pm); hence a slower absorption rate was expected in
comparison
with that reported after IN administration (tõ for IN fentanyl 4.2 to 11.4
minutes versus 54.6
minutes for SL fentanyl in this study).
[0002891 The high bioavailability of fentanyl from the wafer suggests that
wafer fentanyl is
reliably absorbed sublingually and less likely to be partially swallowed,
hence avoiding first-
pass metabolism. No attempt was made to apportion bioavallabillty to these
routes of

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absorption in this study. The analgesic efficacy of the wafer formulation
appears satisfactory,
on the basis of an earlier pilot study conducted among postoperative surgical
patients.
[000290) This SL fentanyl wafer resulted in rapidly detectable plasma fentanyl
concentrations In healthy volunteers, within 10 minutes of administration,
indicating potential
for the treatment of breakthrough pain. The bioavallability was 78.9% in
relation to IV
administration.
=